Tratamento da epilepsia idiopática canina - quadro clínico após interação medicamentosa / Treatment of canine idiopathic epilepsy - clinical picture after drug interaction

Background: The large number of diseases demand perennial development of the pharmaceutical industry. The drugtesting phase is essential to make them available safely. Awareness of pharmacological properties, adverse effects and drug interactions is required. Drug interactions are common in veterinary medicine and should be avoided. At times, epileptic seizures require polydrug therapy, predisposing patients to drug interactions. The interaction between carbamazepine and phenobarbital reported in the literature is an example. The aim of this paper is to report a clinical picture of drug interaction in the treatment of idiopathic epilepsy. Case: A 1-year-old Border Collie male dog, was admitted at the Veterinary Hospital of the Federal University of Lavras in post-ictal. The tutor reported that a year ago the animal had epileptic seizures and clusters with intervals of 21 to 25 days. Despite the continued use of previously prescribed phenobarbital (7.4 mg/kg, v.o., BID, until new recommendations) and carbamazepine (7.5 mg/kg, v.o., BID, until new recommendations), seizure control was not achieved. The physical examination indicated, tachypnea, ptialism, mydriasis, intense fatigue, and alienation from the environment. The patient did not respond to the threat-reflex test. Blood count, hepatic and renal blood chemistry, serum electrolyte (potassium, sodium, calcium and phosphorus), and phenobarbital dosages were requested. Based on the animal's history, breed characteristics, and alterations in the physical examination associated with normal results in complementary exams, idiopathic epilepsy was diagnosed. After analyzing the case, it was observed that the inefficiency in the control of seizures was possibly due to the drug interaction between phenobarbital and carbamazepine. Carbamazepine and phenobarbital reciprocally reduce their half-lives. To confirm the raised hypothesis, the serum concentration of carbamazepine was gradually reduced through weaning from its dose administered to the patient. Serial dosage of the concentration of phenobarbital in the bloodstream was performed. As a result, the serum phenobarbital, previously dosed at a concentration of 13.3 mg/dL with concomitant administration of carbamazepine, increased to 22 mg/dL 40 days after the beginning of weaning from carbamazepine (T0), and then to 36 mg/dL 100 days after T0. There was an increase in the concentration of phenobarbital in the bloodstream while the serum concentration of carbamazepine declined. The patient spaced out his seizures to every 50 to 60 days with phenobarbital monotherapy at a dose of 6 mg/kg. Discussion: Efficient control of clusters, such as the reduction of seizures by 50%, was only possible due to the meticulous perception of the possible interaction reported in medicine. Carbamazepine and phenobarbital are P450 isoenzyme inducers. The concomitant administration of both drugs potentiated the action of isoenzymes in the hepatic microsomal system, which led to an accelerated metabolic processing of the drugs. After weaning from carbamazepine, that is, reducing the action of carbamazepine on the isoenzymes of the P450 enzyme system, the concentration of phenobarbital normalized at 36 mg/ dL. Such concentration is within the reference range reported in the literature: 25 mg/dL to 35 mg/dL of serum phenobarbital for treatment efficacy. Therefore, the control of convulsive crises was achieved. The increase in the concentration of phenobarbital due only to weaning from carbamazepine, even after decreasing the daily dose of barbiturate prescribed to the animal, contributed to evidence of the interaction of these drugs. It is noted that prior knowledge of pharmacological properties, careful study of the patient's history, and the cooperation of the tutor were essential for the therapeutic success and practice of evidence-based veterinary medicine.

Pancitopenia induzida em um cão pelo uso concomitante de fármacos mielotóxicos / Pancytopenia in a dog induced by concomitant use of myelotoxic drugs

Background: The indiscriminate use of drugs is an issue in Veterinary Medicine, as it has serious consequences for theanimals. Many drugs are myelotoxic and cause a decrease in the production of blood cells, which may be irreversible insome cases. The present work reports a case of pancytopenia induced by the concomitant use of myelotoxic drugs (estrogen, metamizole and phenobarbital) in a dog and describes findings on myelotoxicity, hematological alterations andtreatment success.Case: A 7-year-old Lhasa Apso bitch was referred to the Veterinary Hospital of Federal University of Paraná, Curitibacampus, with hematuria and a history of treatment with phenobarbital [2 mg/kg twice a day (bis in die, BID)], metamizole[25 mg/kg 3 times a day (ter in die, TID)], and use of estrogen hormone (estradiol cypionate). At physical examination, theanimal was normohydrated and exhibited normal palpable lymph nodes, pale mucous membranes, galactorrhea, and a bodytemperature of 36°C. A complete blood count including reticulocyte count and a total plasma protein (TPP) exam wererequested. The results revealed pancytopenia (18% hematocrit, 1,400 total leucocytes/µL, and 22,000 reticulocytes/µL).An abdominal ultrasound exam did not detect any relevant alterations. In view of the results obtained, medullary aplasiawas suspected. A bone marrow aspiration was performed. A myelogram revealed a decrease in cellularity (erythrocyticand granulocytic hypoplasia), with presence of rare erythroid and granulocytic precursors. The diagnosis was medullaryaplasia. The animal was treated, and the evolution of the hematological alterations was monitored. The treatment consistedof administration of erythropoietin (100UI/kg subcutaneously every 48 h), prednisone (2 mg/kg BID), Leucogen (3 mg/kg BID), interferon (0.2 IU/kg BID) and Eritrós Dog Tabs [1 tablet once a day (semel in die, SID)]. After 5 days of treatment, the...

Pancitopenia induzida em um cão pelo uso concomitante de fármacos mielotóxicos / Pancytopenia in a dog induced by concomitant use of myelotoxic drugs

Background: The indiscriminate use of drugs is an issue in Veterinary Medicine, as it has serious consequences for theanimals. Many drugs are myelotoxic and cause a decrease in the production of blood cells, which may be irreversible insome cases. The present work reports a case of pancytopenia induced by the concomitant use of myelotoxic drugs (estrogen, metamizole and phenobarbital) in a dog and describes findings on myelotoxicity, hematological alterations andtreatment success.Case: A 7-year-old Lhasa Apso bitch was referred to the Veterinary Hospital of Federal University of Paraná, Curitibacampus, with hematuria and a history of treatment with phenobarbital [2 mg/kg twice a day (bis in die, BID)], metamizole[25 mg/kg 3 times a day (ter in die, TID)], and use of estrogen hormone (estradiol cypionate). At physical examination, theanimal was normohydrated and exhibited normal palpable lymph nodes, pale mucous membranes, galactorrhea, and a bodytemperature of 36°C. A complete blood count including reticulocyte count and a total plasma protein (TPP) exam wererequested. The results revealed pancytopenia (18% hematocrit, 1,400 total leucocytes/µL, and 22,000 reticulocytes/µL).An abdominal ultrasound exam did not detect any relevant alterations. In view of the results obtained, medullary aplasiawas suspected. A bone marrow aspiration was performed. A myelogram revealed a decrease in cellularity (erythrocyticand granulocytic hypoplasia), with presence of rare erythroid and granulocytic precursors. The diagnosis was medullaryaplasia. The animal was treated, and the evolution of the hematological alterations was monitored. The treatment consistedof administration of erythropoietin (100UI/kg subcutaneously every 48 h), prednisone (2 mg/kg BID), Leucogen (3 mg/kg BID), interferon (0.2 IU/kg BID) and Eritrós Dog Tabs [1 tablet once a day (semel in die, SID)]. After 5 days of treatment, the...(AU)

Laboratory evaluation and serum level of phenobarbital administered by different pathways in dogs / Avaliação laboratorial e nível sérico do fenobarbital administrado por diferentes vias em cão

Background: Anticonvulsants are widely used in the treatment of small animals for the remission of isolated seizures and recurrent seizures in epilepsy, including tonic-clonic seizures and in status epileticus. Phenobarbital is the drug of choice for the management of epileptic seizures, it is considered very effective, safe, low cost and with few side effects. Several routes of administration may be used, with the oral, intravenous and intramuscular routes being the most common, with rectal and nasal routes being the least common.Materials, Methods & Results: Twenty mongrel dogs were used in the present study (aged 1 to 6-year-old, males and females, weighing 6.0 to 17.0 kg). The patients were previously evaluated via physical examination, temperature, respiratory and heart rate, laboratory tests (erythrogram and leukogram), and serum biochemistry by analyzing the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (FA), and gammaglutamyltransferase (GGT). Four experimental groups were established with five animals in each group: animals receiving intramuscular injections of phenobarbital (VIM), animals receiving nasal administration of phenobarbital (VN), animals receiving rectal administration of phenobarbital (VR), and animals receiving oral administration of phenobarbital (VO). Phenobarbital was administered every 12 h for 15 days. To determine the serum level of phenobarbital, 5 mL of jugular vein blood was collected in vacuum tubes for evaluation via hemogram. The serum level was determined after 15 days of continuous administration of phenobarbital, as stable phenobarbital serum levels can only be achieved from 10 to 15 days after the first administration. For the serum biochemistry evaluation, 10 mL of blood from the jugular vein was collected using vacuum syringes for assessing ALT, AST, GGT, and FA levels.[...]

Laboratory evaluation and serum level of phenobarbital administered by different pathways in dogs / Avaliação laboratorial e nível sérico do fenobarbital administrado por diferentes vias em cão

Background: Anticonvulsants are widely used in the treatment of small animals for the remission of isolated seizures and recurrent seizures in epilepsy, including tonic-clonic seizures and in status epileticus. Phenobarbital is the drug of choice for the management of epileptic seizures, it is considered very effective, safe, low cost and with few side effects. Several routes of administration may be used, with the oral, intravenous and intramuscular routes being the most common, with rectal and nasal routes being the least common.Materials, Methods & Results: Twenty mongrel dogs were used in the present study (aged 1 to 6-year-old, males and females, weighing 6.0 to 17.0 kg). The patients were previously evaluated via physical examination, temperature, respiratory and heart rate, laboratory tests (erythrogram and leukogram), and serum biochemistry by analyzing the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (FA), and gammaglutamyltransferase (GGT). Four experimental groups were established with five animals in each group: animals receiving intramuscular injections of phenobarbital (VIM), animals receiving nasal administration of phenobarbital (VN), animals receiving rectal administration of phenobarbital (VR), and animals receiving oral administration of phenobarbital (VO). Phenobarbital was administered every 12 h for 15 days. To determine the serum level of phenobarbital, 5 mL of jugular vein blood was collected in vacuum tubes for evaluation via hemogram. The serum level was determined after 15 days of continuous administration of phenobarbital, as stable phenobarbital serum levels can only be achieved from 10 to 15 days after the first administration. For the serum biochemistry evaluation, 10 mL of blood from the jugular vein was collected using vacuum syringes for assessing ALT, AST, GGT, and FA levels.[...](AU)

Aspectos terapêuticos de cães com diagnóstico presuntivo de epilepsia idiopática / Therapeutic aspects of dogs with presumptive diagnosis of idiopathic epilepsy

Background: Epilepsy is a chronic neurological condition characterised by recurrent epileptic seizures. Various antiepileptic drugs are used for the management of canine idiopathic epilepsy. Phenobarbital is the drug of choice for long-term treatment in dogs. Although it is well tolerated, phenobarbital can cause liver injury if administered alone or in combination with other drugs. Therefore, the main of this study was to identify dogs with presumptive diagnosis of idiopathic epilepsy and information about the antiepileptic drugs, the dose and frequency of administration, period of treatment, frequency of the seizure before and after start the treatment, complementary exams and adverse effects. Materials, Methods & Results: In this study were included 21 dogs with idiopathic epilepsy. All dogs were examined and having blood taken for blood count, biochemical tests (ALT, AST, AP, total protein, albumin, creatinine, urea, amylase, lipase, cholesterol and triglycerides), measurement of serum phenobarbital and/or potassium bromide and, some dogs, free T4 by dialysis and canine TSH. In this study, it was observed monotherapy (phenobarbital) in 76.19% (16/21), double therapy (phenobarbital and potassium bromide) in 19.05% (4/21) and triple therapy (phenobarbital, potassium bromide and gabapentin) in 4.76% (1/21) of dogs. The phenobarbital was used as monotherapy with dose between 1.4 and 12 mg kg-1 and the median of serum concentration was 26.41 μg kg-1. There was significant reduction in the frequency of the seizure after start the treatment. There was refractory to antiepileptic drugs in two dogs (9.5%). In blood analysis, there was increase serum activities of AP (23.81%) and ALT (14.20%), decrease total protein (42.29%), hypoalbuminemia (9.5%) and it was not increased AST activities. The main adverse effects were nodularliver damage and hypothyroidism. [...]

Aspectos terapêuticos de cães com diagnóstico presuntivo de epilepsia idiopática / Therapeutic aspects of dogs with presumptive diagnosis of idiopathic epilepsy

Background: Epilepsy is a chronic neurological condition characterised by recurrent epileptic seizures. Various antiepileptic drugs are used for the management of canine idiopathic epilepsy. Phenobarbital is the drug of choice for long-term treatment in dogs. Although it is well tolerated, phenobarbital can cause liver injury if administered alone or in combination with other drugs. Therefore, the main of this study was to identify dogs with presumptive diagnosis of idiopathic epilepsy and information about the antiepileptic drugs, the dose and frequency of administration, period of treatment, frequency of the seizure before and after start the treatment, complementary exams and adverse effects. Materials, Methods & Results: In this study were included 21 dogs with idiopathic epilepsy. All dogs were examined and having blood taken for blood count, biochemical tests (ALT, AST, AP, total protein, albumin, creatinine, urea, amylase, lipase, cholesterol and triglycerides), measurement of serum phenobarbital and/or potassium bromide and, some dogs, free T4 by dialysis and canine TSH. In this study, it was observed monotherapy (phenobarbital) in 76.19% (16/21), double therapy (phenobarbital and potassium bromide) in 19.05% (4/21) and triple therapy (phenobarbital, potassium bromide and gabapentin) in 4.76% (1/21) of dogs. The phenobarbital was used as monotherapy with dose between 1.4 and 12 mg kg-1 and the median of serum concentration was 26.41 μg kg-1. There was significant reduction in the frequency of the seizure after start the treatment. There was refractory to antiepileptic drugs in two dogs (9.5%). In blood analysis, there was increase serum activities of AP (23.81%) and ALT (14.20%), decrease total protein (42.29%), hypoalbuminemia (9.5%) and it was not increased AST activities. The main adverse effects were nodularliver damage and hypothyroidism. [...](AU)

Avaliação da concentração sérica de fenobarbital após administração de doses altas em pacientes com crises convulsivas agrupadas ou em estado epiléptico

Convulsao e a manifestacao neurologica mais comum dos caes e nao e uma doenca especifica, pois pode ser causada por diferentes etiologias, como genetica, estrutural ou desconhecida. Inicia-se a terapia com anticonvulsivantes em pacientes como crises agrupadas ou estado epileptico, antes mesmo da causa ser elucidada. O fenobarbital e a droga de primeira escolha como terapia anticonvulsivante. Recomenda-se a dose inicial de 2,5 mg/kg a cada 12 horas, que leva de 10 a 15 dias para atingir concentracao serica estavel. Em animais que apresentam convulsoes agrupadas ou estado epileptico, o FB pode ser administrado na dose de ataque 15-20 mg/kg pelas vias intravenosa, intramuscular ou oral, dividida em multiplas doses de 3-5 mg/kg ao longo de 24-48 horas, para se alcancar a concentracao serica desejada de forma mais rapida. A concentracao serica pode ser mensurada um a tres dias apos essa dose de ataque. Realizou-se um estudo clinico prospectivo e transversal com caes com o objetivo de comparar a concentracao serica de fenobarbital obtida apos 48 horas com a administracao do fenobarbital na dose de 3mg/kg/TID (D2) com aquela obtida 15 dias apos o momento do inicio da terapia (D15). Tambem verificou se ha correlacao entre as doses de fenobarbital e o efeito sobre as enzimas hepaticas (ALT e FA), albumina, triglicerides, colesterol, ureia e creatinina. Para isso, foram estudados 22 caes, de varias racas e idades, ambos os sexos, sendo femeas e machos apresentados ao Hospital Veterinario da Universidade de Sao Paulo por ocasiao da primeira crise convulsiva e que nao haviam sido submetidos a nenhum tratamento previo com o farmaco. Os achados do estudo mostraram que houve uma estabilidade entre as concentracoes sericas do D2 e D15. As concentracoes de FA, colesterol e ureia apresentaram um aumento apos 15 dias de tratamento, porem a ureia estatisticamente nao tem diferenca entre a primeira e ultima dosagem. Concluindo que um regime de dosagem diferente parece ser benefico e seguro para pacientes epilepticos como uma opcao adicional para o clinico que trata casos epilepticos potencialmente desafiadores por serem emergencias.

Seizure is the most common neurological manifestation in dogs and is not a specific disease as it can be caused by different etiologies such as genetic, structural or idiopathic. Anticonvulsant therapy is initiated in patients with cluster seizures or status epilepticus, even before the cause is elucidated. Phenobarbital is the first line drug choice as anticonvulsant therapy. The recommended starting dose of 2.5 mg/kg every 12 hours. and it takes 10 to 15 days to achieve stable serum concentration. In animals presenting with cluster seizures or status epilepticus, phenobarbital may be administered at the attack dose of 15-20 mg/kg intravenously, intramuscularly or orally, divided into multiple doses of 3-5 mg/kg over 24-48 hours to reach the desired serum concentration faster. Serum concentration of phenobarbital can be measured in 1 to 3 days after the initial attack dose. A prospective cross-sectional clinical trial was performed in dogs to compare the phenobarbital serum concentration obtained 48 hours after the administration of phenobarbital at a dose of 3mg/kg TID (D2) to that obtained 15 days after institution of therapy (D15). The correlation between phenobarbital doses and the effect on liver enzymes (ALT and ALP), albumin, triglycerides, cholesterol, urea and creatinine was also evaluated. The study included 22 dogs of different breeds, age and gender presenting to the Veterinary Teaching Hospital of the University of Sao Paulo during the first seizure episode and who had not undergone any previous treatment with phenobarbital. Results demonstrated a stability in serum concentration of phenobarbital between D2 and D15. Levels of ALP, cholesterol and BUN increased after 15 days of treatment, but BUN levels were not statistically significant. In conclusion, this dosing regimen of phenobarbital appears to be beneficial and safe option for the clinician treating potentially challenging epileptic cases

Estudo da variação da concentração sérica de fenobarbital em cães cronicamente medicados / Study of the variation in the serum concentrations of phenobarbital in dogs exposured to a long term treatment

Com a finalidade de avaliar a variação na concentração sérica do fenobarbital durante um intervalo de 12 horas da sua administração, as concentrações séricas foram mensuradas a cada duas horas em 30 cães cronicamente medicados, durante no mínimo um mês. A determinação dos valores séricos de fenobarbital, por meio de Imunofluorescência polarizada. Os valores de meia-vida obtidos variaram de 13-131 horas, sendo que a maioria dos cães atingiram o estado de equilíbrio dinâmico por volta de 15 dias, e todos após quatro semanas, recomendando-se assim monitoração após quatro semanas do início da terapia ou após cada ajuste de dose. Houve diferença significante entre as médias das amostras coletadas duas e quatro horas (pico) com as das amostras coletadas imediatamente antes e oito, 10 e 12 horas após sua administração. Assim, para a monitoração, pode-se realizar a coleta sangüínea, imediatamente antes da administração do fenobarbital, ou em qualquer horário, entre oito a 12 horas após sua administração e nos casos suspeitos de intoxicação uma segunda amostra pode ser coletada dentro de duas a quatro horas após a sua administração.(AU)

In order to evaluate daily changes of concentration of phenobarbital during the interval of 12 hours of its administration, serum phenobarbital concentration were measured each two hours in 30 dogs submitted to the referred drug therapy for at least one month. All serum phenobarbital drug concentration were determined by use of a fluorecence polarization immunoassay. The values of half-lives obtained varied from 13 to 131 hours, most dogs reached steaty state serum concentrations by 15 days, and all dogs after four weeks. Therefore, clinicians should monitor serum phenobarbital concentrations four weeks after initiating treatment or after a change in dosage. There was significant difference among the averages of the samples two and four hours (peak) with the ones samples colected immediately before, and eight, 10 and 12 hours after its administration. In order to monitore serum phenobarbital concentrarions, its is suggest that blood collection is measured just before the dose or at any time between eight and 12 hours after its administration. If a concern arises regarding toxicity, a second sample should be colleted between two and four hours after phenobarbital administration.(AU)

Alguns eventos morfológicos do processo de reparo de falha óssea diafisária no rádio esquerdo de ratos tratados com fenobarbital / Some morphological events of the healing of diaphisary bone failure in the left radius of rats under phenobarbital treatment

O objetivo deste trabalho foi investigar os efeitos morfológicos do tratamento prolongado com fenobarbital, na consolidação de falha óssea diafisária, induzida no rádio esquerdo de rato. Ratos machos albinos da linhagem Wistar, com 40 dias de idade, foram divididos em dois grupos. O grupo experimental foi tratado com fenobarbital (Gardenal®) na dose de 105 mg/kg de peso corpóreo, por via subcutânea, no período de até 90 dias. O grupo controle foi tratado, de modo similar, com solução de NaCl 0,9 por cento. No 30º dia de tratamento, os animais foram submetidos a cirurgia para produção de falha óssea diafisária de 2 mm, no rádio esquerdo. Após 20, 40 e 60 dias de cirurgia, os ratos foram sacrificados por inalação de éter etílico, e o rádio esquerdo foi coletado, fixado e processado para rotina histológica de microscopia óptica com análises morfométricas. As falhas ósseas diafisárias dos ratos experimentais mostravam menor fração de volume de tecido ósseo neoformado, comparativamente com as falhas ósseas diafisárias dos ratos controle. Os resultados observados foram indicativos de que o tratamento prolongado com fenobarbital inibe a osteogênese em osso longo, retardando o processo de reparo de falha óssea diafisária em rato. (AU)

Avaliação clínica, laboratorial e radiológica de filhotes de cães submetidos ao uso de fenobarbital

O fenobarbital é o medicamento mais utilizado para o tratamento da epilepsia canina no Brasil.O objetivo desse trabalho foi analisar as conseqüências do uso do fenobarbital através da avaliação clínica dos animais, avaliação comportamental, determinação dos parâmetros hematológicos, determinação dos parâmetros bioquímicos, avaliação hormonal, avaliação radiológica e avaliação ultrassonográfica dos órgãos abdominais. Os filhotes de cães tornaram-se alvo deste estudo devido a escassez de dados na literatura. Foram utilizados 12 filhotes de cães com idade inicial de aproximadamente 60 dias, divididos em dois grupos, o grupo controle que não recebia medicamento e o grupo tratamento que recebia o fenobarbital na dose de 4mg/kg a cada 12 horas durante seis meses. No período compreendido entre junho de 2004 e janeiro de 2005 foram realizadas colheitas de sangue para avaliações hematológicas (eritrograma e leucograma) e bioquímicas (uréia, creatinina, fosfatase alcalina, aspartato am inotransferase, alanina aminotransferase e colesterol) e hormonais (dosagem de tiroxina livre). No período do experimento também foram realizadas avaliações radiológicas, através da radiografia da parte distal da ulna e ultra-sonografia abdominal e avaliação comportamental. Dentre os parâmetros hematológicos avaliados, houve diferença significativa no valor do hematócrito, que se mostrou diminuído no grupo tratamento, assim como os valores de hemácias e hemoglobina. Para as variáveis bioquímicas houve diferença estatística significativa entre os grupos em relação á uréia, ALT. Na análise comportamental os animais do grupo tratamento mostraram-se hiperativos. Nas radiografias da ulna não foram observadas alterações, contudo na ultra-sonografia abdominal, foi observada uma hiperecogenicidade do fígado em relação ao córtex renal nos animais do grupo tratamento. Na avaliação hormonal também houve diferença significativa para os valores de T4 livre. Por meio desta pesquisa foi possível verificar as conseqüências do uso de fenobarbital em filhotes de cães. O animal que recebe o fenobarbital pode apresentar hiperatividade, lesões de pele alérgicas do tipo maculo-papulares, hepatopatia, diminuição dos níveis de tiroxina livre, portanto o filhote de cão tratado com o fenobarbital deve ser monitorado, no aspecto clínico, comportamental, laboratorial e através da ultra-sonografia abdominal para detectar os efeitos colaterais precocemente