RESUMO

Opioids are potent analgesics and are believed to be the best choice for moderate and severe nociceptive pain. Investigating all the possible administration route options for pain management in the different animal species is warranted in horses as systemic administration of these drugs in horses is difficult. In this study the authors describe for the first time in the literature the administration of methadone orally to MDR1 genotipically normal horses. Twelve adult healthy horses (6 females and 6 males) were studied. Horses randomly received one of the doses of methadone (0.1, 0.2, and 0.4mg/kg) per os, which was administered using a 60cc syringe containing 30ml of corn syrup The results showed all doses produced plasma levels compatible to analgesic plasma levels in human beings. The authors conclude that methadone is absorbed when orally administered in horses at doses of 0.1, 0.2, and 0.4 mg.kg -1. It does not produce excitement, sedation, nor undesirable side effects in healthy horses. Further studies are necessary in order to establish clinical guidelines for oral methadone as an alternative for pain management in the horse.

RESUMO

Opioids are potent analgesics and are believed to be the best choice for moderate and severe nociceptive pain. Investigating all the possible administration route options for pain management in the different animal species is warranted in horses as systemic administration of these drugs in horses is difficult. In this study the authors describe for the first time in the literature the administration of methadone orally to MDR1 genotipically normal horses. Twelve adult healthy horses (6 females and 6 males) were studied. Horses randomly received one of the doses of methadone (0.1, 0.2, and 0.4mg/kg) per os, which was administered using a 60cc syringe containing 30ml of corn syrup The results showed all doses produced plasma levels compatible to analgesic plasma levels in human beings. The authors conclude that methadone is absorbed when orally administered in horses at doses of 0.1, 0.2, and 0.4 mg.kg -1. It does not produce excitement, sedation, nor undesirable side effects in healthy horses. Further studies are necessary in order to establish clinical guidelines for oral methadone as an alternative for pain management in the horse.

RESUMO

Opioids are potent analgesics and are believed to be the best choice for moderate and severe nociceptive pain. Investigating all the possible administration route options for pain management in the different animal species is warranted in horses as systemic administration of these drugs in horses is difficult. In this study the authors describe for the first time in the literature the administration of methadone orally to MDR1 genotipically normal horses. Twelve adult healthy horses (6 females and 6 males) were studied. Horses randomly received one of the doses of methadone (0.1, 0.2, and 0.4mg/kg) per os, which was administered using a 60cc syringe containing 30ml of corn syrup The results showed all doses produced plasma levels compatible to analgesic plasma levels in human beings. The authors conclude that methadone is absorbed when orally administered in horses at doses of 0.1, 0.2, and 0.4 mg.kg -1. It does not produce excitement, sedation, nor undesirable side effects in healthy horses. Further studies are necessary in order to establish clinical guidelines for oral methadone as an alternative for pain management in the horse.

RESUMO

Opioids are potent analgesics and are believed to be the best choice for moderate and severe nociceptive pain. Investigating all the possible administration route options for pain management in the different animal species is warranted in horses as systemic administration of these drugs in horses is difficult. In this study the authors describe for the first time in the literature the administration of methadone orally to MDR1 genotipically normal horses. Twelve adult healthy horses (6 females and 6 males) were studied. Horses randomly received one of the doses of methadone (0.1, 0.2, and 0.4mg/kg) per os, which was administered using a 60cc syringe containing 30ml of corn syrup The results showed all doses produced plasma levels compatible to analgesic plasma levels in human beings. The authors conclude that methadone is absorbed when orally administered in horses at doses of 0.1, 0.2, and 0.4 mg.kg -1. It does not produce excitement, sedation, nor undesirable side effects in healthy horses. Further studies are necessary in order to establish clinical guidelines for oral methadone as an alternative for pain management in the horse.

RESUMO

Opioids are potent analgesics and are believed to be the best choice for moderate and severe nociceptive pain. Investigating all the possible administration route options for pain management in the different animal species is warranted in horses as systemic administration of these drugs in horses is difficult. In this study the authors describe for the first time in the literature the administration of methadone orally to MDR1 genotipically normal horses. Twelve adult healthy horses (6 females and 6 males) were studied. Horses randomly received one of the doses of methadone (0.1, 0.2, and 0.4mg/kg) per os, which was administered using a 60cc syringe containing 30ml of corn syrup The results showed all doses produced plasma levels compatible to analgesic plasma levels in human beings. The authors conclude that methadone is absorbed when orally administered in horses at doses of 0.1, 0.2, and 0.4 mg.kg -1. It does not produce excitement, sedation, nor undesirable side effects in healthy horses. Further studies are necessary in order to establish clinical guidelines for oral methadone as an alternative for pain management in the horse.

RESUMO

Opioids are potent analgesics and are believed to be the best choice for moderate and severe nociceptive pain. Investigating all the possible administration route options for pain management in the different animal species is warranted in horses as systemic administration of these drugs in horses is difficult. In this study the authors describe for the first time in the literature the administration of methadone orally to MDR1 genotipically normal horses. Twelve adult healthy horses (6 females and 6 males) were studied. Horses randomly received one of the doses of methadone (0.1, 0.2, and 0.4mg/kg) per os, which was administered using a 60cc syringe containing 30ml of corn syrup The results showed all doses produced plasma levels compatible to analgesic plasma levels in human beings. The authors conclude that methadone is absorbed when orally administered in horses at doses of 0.1, 0.2, and 0.4 mg.kg -1. It does not produce excitement, sedation, nor undesirable side effects in healthy horses. Further studies are necessary in order to establish clinical guidelines for oral methadone as an alternative for pain management in the horse.

RESUMO

The study was done to compare the heart rate, arterial blood pressure, arterial blood gases, respiratory rate, body temperature, and behavior after subarachnoid administration of hyperbaric morphine (MorphineD10), buprenorphine (BuprenorphineD10), methadone (Methadone D10), and 10% dextrose (D10) in conscious horses. Six adult horses were studied. Treatments were administered into the lombo-sacral subarachnoid space through an epidural catheter, MorphineD10 at 0.01mg kg-1, BuprenorphineD10 at 0.001mg kg-1, MethadoneD10 at 0.01mg kg-1, and 10% dextrose as a control group. The results showed that there are minimum changes in heart and respiratory rate, blood gases, blood pressure, and body temperature after subarachnoid administration of hyperbaric opioids in horses. No sedation and nor motor impairment or behavioral changes occur.

O estudo foi realizado com a finalidade de comparar a freqüência cardíaca, a pressão sanguínea arterial, à análise de gases, a freqüência respiratória, a temperatura corpórea e o comportamento de eqüinos após a administração subaraquenóide de morfina hiperbárica (MorfinaD10), buprenorfina hiperbárica (BuprenorfinaD10), metadona hiperbárica (MetadonaD10) e dextrose 10% (D10). As doses de MorphinaD10 (0.01mg kg-1), BuprenorfinaD10 (0.001mg kg-1), MetadonaD10 (0.01mg kg-1) e dextrose 10% (grupo controle, 5ml) foram administradas no espaço subaracnóide da região lombo-sacra de seis cavalos adultos, por meio de um catéter epidural. Os resultados mostraram alterações mínimas nas freqüências cardíaca e respiratória, na análise de gases, na pressão arterial e na temperatura corpórea após a administração subaracnóide de opióides hiperbáricos em cavalos. Os animais não apresentaram sedação, ataxia nem alteração comportamental.

RESUMO

(MDR1) gene expressed in tumor cells and also in several normal tissues, such as intestine, liver, kidney, blood-brain barrier, spinal cord, and placenta. P-gp has been identified in mice, rat, bovine, monkey, rodents, and human beings and has been receiving a particular clinical relevance because this protein expression limits brain access and intestinal absorption of many drugs. This protein plays a role as a protective barrier against a wide variety of substrates, avoiding drug entry into the central nervous system. P-glycoprotein also interferes with drug bioavailability and disposition, including absorption, distribution, metabolization, and excretion, influencing pharmacokinetic and pharmacodynamic of drugs. Modulation of P-gp may help the efficacy of treatment of several diseases and can explain some adverse central nervous system effects induced by drugs after intravenous administration and the poor response of oral administration in patients. Alteration in P-gp expression or function has been associated with several diseases susceptibility in humans and animals. Furthermore, additional studies relating MDR1 and P-gp expression has an important clinical implication also in terms of treatment efficacy.

P-glicoproteína (P-gp) é um transportador de membrana ligado ao gene de resistência múltipla (MDR1), expressado em células tumorais e também em tecidos normais como intestino, fígado, rins, membranas hematoencefálica, hemo-placentária e medula espinhal. A P-gp já foi identificada em camundongos, ratos, bovinos, macacos, roedores e seres humanos e tem ganhado relevância clínica particular em função de sua expressão limitar o acesso de drogas ao cérebro e interferir com a absorção intestinal quando administradas pela via oral. Esta proteína participa da função protetora do organismo contra uma grande variedade de substratos, evitando a entrada de drogas no sistema nervoso central. A P-gp interfere também com a biodisponibilidade dos fármacos, incluindo absorção, distribuição, metabolização e excreção, influenciando assim, a farmacocinética e dinâmica dos mesmos. Desta maneira, a modulação da P-gp pode explicar alguns efeitos adversos no sistema nervoso central, induzidos por alguns fármacos após administração intravenosa, e a pobre resposta após administração oral em pacientes. A alteração na expressão ou função da P-glicoproteína tem sido associada a uma maior susceptibilidade a diversas doenças em humanos e animais. Estudos adicionais relacionados à expressão e à função da P-gp espécie-específica têm implicação clínica importante em termos de eficiência de tratamento.

RESUMO

Opioid absorption in the intestinal tract as well as its effects in the central nervous system is modulated by the P-glycoprotein (P-gp) encoded in the Multi-drug Resistance gene (MDR1) also named ATP-binding cassete, subfamily B, member 1 (ABCB1). This MDR1 gene acts as a selective pump. The expression of this protein in humans and rodents inhibits cellular uptake of substrate opioids. The presence of the intestinal iso-enzyme CYP3A4 associated with MDR1 gene decreases the opioid analgesic activity due to an increase in intestinal metabolism, with a predicted intestinal first pass extraction around 20% which significantly influences the oral availability of opioids. In the central nervous system, P-gp expression decreases opioid neuronal uptake diminishing the analgesic effects. It is unknown if horses have the MDR1 gene and P-gp and what are the effects on opioid absorption, metabolism, and analgesia. Identifying the MDR1 gene and P-gp status in horses is of great importance in order to better understand opioid pharmacologic effects in horses.

A absorção de opióides no trato intestinal, assim como seus efeitos no sistema nervoso central, são modulados pela P-glicoproteína (P-gp), uma proteína de membrana celular codificada pelo gene MDR1, também chamado ATP-binding cassete, subfamília B, membro 1 (ABCB1) e que atua como bomba seletiva. A expressão desta proteína em roedores e seres humanos inibe a absorção celular de opióides e sua presença no intestino associada à isoenzima CYP3A4 reduz a atividade analgésica dos opióides por ativação do metabolismo intestinal do fármaco. A redução na extração intestinal de fármacos opióides susceptíveis a esta proteína chega a 20%, o que reduz significativamente a biodisponibilidade de opióides administrados por via oral. No sistema nervoso central, a P-gp diminui a captação neuronal dos opióides e seus efeitos analgésicos. Ainda é desconhecido se o gene MDR1 e a P-gp estão presentes no trato intestinal e no sistema nervoso central em cavalos e quais os seus efeitos na absorção, metabolismo e efeito analgésico nesta espécie. Fica evidente a importância da determinação da presença ou não deste gene e sua expressão protéica no cavalo, para um melhor entendimento da farmacologia dos opióides nesta espécie.

RESUMO

This study is the first to report the use of spinal hyperbaric opioids in horses injected through a lumbar-sacral subarachnoid catheter. The injection of hyperbaric subarachnoid morphine and methadone produced short term intense analgesia over the dermatomes of the perineal, sacral, lumbar, and thoracic areas without cardiorespiratory depression, ataxia or central nervous system excitement. The technique involves the use of 10% dextrose as a hyperbaric solvent producing an average hyperbaric solution with a specific gravity of 1030. The use of spinal hyperbaric opioids in horses can be recommended for short term moderate to severe pain management in this species.

Este estudo relata pela primeira vez o uso de opioide hiperbárico por via espinhal em cavalos, administrado através de um cateter subaraquenóide lombo-sacro. Foi demonstrado que a administração de morfina ou metadona hiperbáricos em solução de dextrose 10% produz analgesia intensa e de curta duração sobre os dermatomas perineais, sacrais, lombares e torácicos, sem depressão cardiorrespiratória, ataxia ou excitação do sistema nervoso central. A técnica descrita, neste estudo, produziu soluções com gravidade específica de 1030. O uso de solução hiperbárica de opióides pode ser recomendado para obtenção de analgesia intensa de curta duração no cavalo.

RESUMO

P-glycoprotein (P-gp) is a membrane transporter encoded in the Multi-drug Resistance (MDR1) gene expressed in several normal tissues and over expressed in tumor cells. P-gp was already identified in different species but not yet in equine. MDR1 gene and P-gp are able to interfere with bioavailability and disposition of several drugs, altering pharmacokinetic and pharmacodinamic of drugs. The presence of the MDR1 and P-gp in the central nervous system blocks the entry of certain drugs in this tissue and reduces drug absorption and enhances drug elimination when P-gp and MDR1 are presented in the gastrointestinal tract. This study showed that the MDR1 gene is present in equine ileum. Future studies on the impact of the P-glycoprotein encoded gene MDR1 on drugs pharmacologic effects in horses are granted.

P-glicoproteína (P-gp) é uma membrana de transporte expressa pelo gene de resistência múltipla (MDR1), presente em diversos tecidos e normais e células tumorais. Embora o gene MDR1 e a P-gp já tenham sido identificados em diferentes espécies, ainda não se têm informações com relação à especie equina. O gene MDR1 e a P-gp são capazes de interferir com a bioviabilidade e a disposição de diversos fármacos, alterando a farmacocinética e a farmacodinâmica dos mesmos. A presença do gene MDR1 e da P-gp no sistema nervoso central impede a entrada de certos fármacos neste tecido e, no trato gastrointestinal, eles reduzem a absorção de fármacos e aumentam sua eliminação. Neste estudo, comprovou-se pela primeira vez, a presença do gene MDR1 no íleo de eqüinos. Sugere-se que estudos futuros sejam realizados para a determinação do impacto da presença da P-glicoproteína nos efeitos de diversos fármacos em eqüinos.

RESUMO

P-glycoprotein (P-gp) is a membrane transporter encoded in the Multi-drug Resistance (MDR1) gene expressed in several normal tissues and over expressed in tumor cells. P-gp was already identified in different species but not yet in equine. MDR1 gene and P-gp are able to interfere with bioavailability and disposition of several drugs, altering pharmacokinetic and pharmacodinamic of drugs. The presence of the MDR1 and P-gp in the central nervous system blocks the entry of certain drugs in this tissue and reduces drug absorption and enhances drug elimination when P-gp and MDR1 are presented in the gastrointestinal tract. This study showed that the MDR1 gene is present in equine ileum. Future studies on the impact of the P-glycoprotein encoded gene MDR1 on drugs pharmacologic effects in horses are granted.

P-glicoproteína (P-gp) é uma membrana de transporte expressa pelo gene de resistência múltipla (MDR1), presente em diversos tecidos e normais e células tumorais. Embora o gene MDR1 e a P-gp já tenham sido identificados em diferentes espécies, ainda não se têm informações com relação à especie equina. O gene MDR1 e a P-gp são capazes de interferir com a bioviabilidade e a disposição de diversos fármacos, alterando a farmacocinética e a farmacodinâmica dos mesmos. A presença do gene MDR1 e da P-gp no sistema nervoso central impede a entrada de certos fármacos neste tecido e, no trato gastrointestinal, eles reduzem a absorção de fármacos e aumentam sua eliminação. Neste estudo, comprovou-se pela primeira vez, a presença do gene MDR1 no íleo de eqüinos. Sugere-se que estudos futuros sejam realizados para a determinação do impacto da presença da P-glicoproteína nos efeitos de diversos fármacos em eqüinos.

RESUMO

This study is the first to report the use of spinal hyperbaric opioids in horses injected through a lumbar-sacral subarachnoid catheter. The injection of hyperbaric subarachnoid morphine and methadone produced short term intense analgesia over the dermatomes of the perineal, sacral, lumbar, and thoracic areas without cardiorespiratory depression, ataxia or central nervous system excitement. The technique involves the use of 10% dextrose as a hyperbaric solvent producing an average hyperbaric solution with a specific gravity of 1030. The use of spinal hyperbaric opioids in horses can be recommended for short term moderate to severe pain management in this species.

Este estudo relata pela primeira vez o uso de opioide hiperbárico por via espinhal em cavalos, administrado através de um cateter subaraquenóide lombo-sacro. Foi demonstrado que a administração de morfina ou metadona hiperbáricos em solução de dextrose 10% produz analgesia intensa e de curta duração sobre os dermatomas perineais, sacrais, lombares e torácicos, sem depressão cardiorrespiratória, ataxia ou excitação do sistema nervoso central. A técnica descrita, neste estudo, produziu soluções com gravidade específica de 1030. O uso de solução hiperbárica de opióides pode ser recomendado para obtenção de analgesia intensa de curta duração no cavalo.

RESUMO

Opioid absorption in the intestinal tract as well as its effects in the central nervous system is modulated by the P-glycoprotein (P-gp) encoded in the Multi-drug Resistance gene (MDR1) also named ATP-binding cassete, subfamily B, member 1 (ABCB1). This MDR1 gene acts as a selective pump. The expression of this protein in humans and rodents inhibits cellular uptake of substrate opioids. The presence of the intestinal iso-enzyme CYP3A4 associated with MDR1 gene decreases the opioid analgesic activity due to an increase in intestinal metabolism, with a predicted intestinal first pass extraction around 20% which significantly influences the oral availability of opioids. In the central nervous system, P-gp expression decreases opioid neuronal uptake diminishing the analgesic effects. It is unknown if horses have the MDR1 gene and P-gp and what are the effects on opioid absorption, metabolism, and analgesia. Identifying the MDR1 gene and P-gp status in horses is of great importance in order to better understand opioid pharmacologic effects in horses.

A absorção de opióides no trato intestinal, assim como seus efeitos no sistema nervoso central, são modulados pela P-glicoproteína (P-gp), uma proteína de membrana celular codificada pelo gene MDR1, também chamado ATP-binding cassete, subfamília B, membro 1 (ABCB1) e que atua como bomba seletiva. A expressão desta proteína em roedores e seres humanos inibe a absorção celular de opióides e sua presença no intestino associada à isoenzima CYP3A4 reduz a atividade analgésica dos opióides por ativação do metabolismo intestinal do fármaco. A redução na extração intestinal de fármacos opióides susceptíveis a esta proteína chega a 20%, o que reduz significativamente a biodisponibilidade de opióides administrados por via oral. No sistema nervoso central, a P-gp diminui a captação neuronal dos opióides e seus efeitos analgésicos. Ainda é desconhecido se o gene MDR1 e a P-gp estão presentes no trato intestinal e no sistema nervoso central em cavalos e quais os seus efeitos na absorção, metabolismo e efeito analgésico nesta espécie. Fica evidente a importância da determinação da presença ou não deste gene e sua expressão protéica no cavalo, para um melhor entendimento da farmacologia dos opióides nesta espécie.

RESUMO

(MDR1) gene expressed in tumor cells and also in several normal tissues, such as intestine, liver, kidney, blood-brain barrier, spinal cord, and placenta. P-gp has been identified in mice, rat, bovine, monkey, rodents, and human beings and has been receiving a particular clinical relevance because this protein expression limits brain access and intestinal absorption of many drugs. This protein plays a role as a protective barrier against a wide variety of substrates, avoiding drug entry into the central nervous system. P-glycoprotein also interferes with drug bioavailability and disposition, including absorption, distribution, metabolization, and excretion, influencing pharmacokinetic and pharmacodynamic of drugs. Modulation of P-gp may help the efficacy of treatment of several diseases and can explain some adverse central nervous system effects induced by drugs after intravenous administration and the poor response of oral administration in patients. Alteration in P-gp expression or function has been associated with several diseases susceptibility in humans and animals. Furthermore, additional studies relating MDR1 and P-gp expression has an important clinical implication also in terms of treatment efficacy.

P-glicoproteína (P-gp) é um transportador de membrana ligado ao gene de resistência múltipla (MDR1), expressado em células tumorais e também em tecidos normais como intestino, fígado, rins, membranas hematoencefálica, hemo-placentária e medula espinhal. A P-gp já foi identificada em camundongos, ratos, bovinos, macacos, roedores e seres humanos e tem ganhado relevância clínica particular em função de sua expressão limitar o acesso de drogas ao cérebro e interferir com a absorção intestinal quando administradas pela via oral. Esta proteína participa da função protetora do organismo contra uma grande variedade de substratos, evitando a entrada de drogas no sistema nervoso central. A P-gp interfere também com a biodisponibilidade dos fármacos, incluindo absorção, distribuição, metabolização e excreção, influenciando assim, a farmacocinética e dinâmica dos mesmos. Desta maneira, a modulação da P-gp pode explicar alguns efeitos adversos no sistema nervoso central, induzidos por alguns fármacos após administração intravenosa, e a pobre resposta após administração oral em pacientes. A alteração na expressão ou função da P-glicoproteína tem sido associada a uma maior susceptibilidade a diversas doenças em humanos e animais. Estudos adicionais relacionados à expressão e à função da P-gp espécie-específica têm implicação clínica importante em termos de eficiência de tratamento.

RESUMO

The study was done to compare the heart rate, arterial blood pressure, arterial blood gases, respiratory rate, body temperature, and behavior after subarachnoid administration of hyperbaric morphine (MorphineD10), buprenorphine (BuprenorphineD10), methadone (Methadone D10), and 10% dextrose (D10) in conscious horses. Six adult horses were studied. Treatments were administered into the lombo-sacral subarachnoid space through an epidural catheter, MorphineD10 at 0.01mg kg-1, BuprenorphineD10 at 0.001mg kg-1, MethadoneD10 at 0.01mg kg-1, and 10% dextrose as a control group. The results showed that there are minimum changes in heart and respiratory rate, blood gases, blood pressure, and body temperature after subarachnoid administration of hyperbaric opioids in horses. No sedation and nor motor impairment or behavioral changes occur.

O estudo foi realizado com a finalidade de comparar a freqüência cardíaca, a pressão sanguínea arterial, à análise de gases, a freqüência respiratória, a temperatura corpórea e o comportamento de eqüinos após a administração subaraquenóide de morfina hiperbárica (MorfinaD10), buprenorfina hiperbárica (BuprenorfinaD10), metadona hiperbárica (MetadonaD10) e dextrose 10% (D10). As doses de MorphinaD10 (0.01mg kg-1), BuprenorfinaD10 (0.001mg kg-1), MetadonaD10 (0.01mg kg-1) e dextrose 10% (grupo controle, 5ml) foram administradas no espaço subaracnóide da região lombo-sacra de seis cavalos adultos, por meio de um catéter epidural. Os resultados mostraram alterações mínimas nas freqüências cardíaca e respiratória, na análise de gases, na pressão arterial e na temperatura corpórea após a administração subaracnóide de opióides hiperbáricos em cavalos. Os animais não apresentaram sedação, ataxia nem alteração comportamental.