RESUMEN
Anesthetics utilized for the immobilization of pregnant mammals are prone to crossing the placental barrier and cause adverse effects to the fetuses. In this study, we develop a facile method employing high performance liquid chromatography (HPLC) for the study of Telazol crossing the placental barrier of pregnant pigs. The method mainly relies on the efficient extraction strategy that includes the mobile phase composed of 10 mM ammonium acetate aqueous solution-acetonitrile (1:4, v/v). When the injected dose of Telazol is 10 mg/kg (5 mg/kg of each constituent drug, zolazepem and tiletamine), zolazepam can cross the placental barrier as it is detected in both uterus and umbilical cord with approximately the same content. Conversely, tiletamine is detected in neither uterus nor umbilical cord, indicating the absence of placental transfer of tiletamine. The different absorption rates of the two dosage-equal compounds by pigs are found to be the main cause of their different abilities to cross the placental barrier.
Asunto(s)
Anestésicos/farmacocinética , Cromatografía Líquida de Alta Presión/veterinaria , Placenta/metabolismo , Porcinos/sangre , Tiletamina/farmacocinética , Zolazepam/farmacocinética , Anestésicos/sangre , Animales , Combinación de Medicamentos , Femenino , Embarazo , Tiletamina/sangre , Útero/metabolismo , Zolazepam/sangreRESUMEN
OBJECTIVE To evaluate the effect of IM administration of a tiletamine hydrochloride-zolazepam hydrochloride (TZ) combination with either dexmedetomidine hydrochloride or saline (0.9% NaCl) solution (SS) on the motor response to claw clamping, selected cardiorespiratory variables, and quality of recovery from anesthesia in alpacas. ANIMALS 5 adult sexually intact male alpacas. PROCEDURES Each alpaca was given the TZ combination (2 mg/kg) with dexmedetomidine (5 [D5], 10 [D10], 15 [D15], or 20 [D20] µg/kg) or SS IM at 1-week intervals (5 experiments); motor response to claw clamping was assessed, and characteristics of anesthesia, recovery from anesthesia, and selected cardiorespiratory variables were recorded. RESULTS Mean ± SEM duration of lack of motor response to claw clamping was longest when alpacas received treatments D15 (30.9 ± 5.9 minutes) and D20 (40.8 ± 5.9 minutes). Duration of lateral recumbency was significantly longer with dexmedetomidine administration. The longest time (81.3 ± 10.4 minutes) to standing was observed when alpacas received treatment D20. Following treatment SS, 4 alpacas moved in response to claw clamping at the 5-minute time point. Heart rate decreased from pretreatment values in all alpacas when dexmedetomidine was administered. Treatments D10, D15, and D20 decreased Pao2, compared with treatment SS, during the first 15 minutes. During recovery, muscle stiffness and multiple efforts to regain a sternal position were observed in 3 SS-treated and 1 D5-treated alpacas; all other recoveries were graded as excellent. CONCLUSIONS AND CLINICAL RELEVANCE In TZ-anesthetized alpacas, dexmedetomidine (10, 15, and 20 µg/kg) administered IM increased the duration of lack of motor response to claw clamping, compared with the effect of SS.
Asunto(s)
Anestésicos/farmacocinética , Camélidos del Nuevo Mundo/metabolismo , Dexmedetomidina/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Hipnóticos y Sedantes/farmacología , Tiletamina/farmacocinética , Zolazepam/farmacocinética , Anestesia/veterinaria , Anestésicos/administración & dosificación , Anestésicos/sangre , Animales , Dexmedetomidina/administración & dosificación , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Hipnóticos y Sedantes/administración & dosificación , Inyecciones Intramusculares/veterinaria , Masculino , Recuperación de la Función , Tiletamina/administración & dosificación , Tiletamina/sangre , Zolazepam/administración & dosificación , Zolazepam/sangreRESUMEN
Serious post-operative neurological complications of unknown aetiology are reported in tigers after immobilisation using tiletamine and zolazepam. These complications may arise from the persistent effects of tiletamine or active metabolites of tiletamine or zolazepam. Concentrations of tiletamine, zolazepam and some metabolites were measured using high performance liquid chromatography-mass spectrometry in plasma from captive tigers (n = 8) and leopards (n = 9; an unaffected species, for comparison) during anaesthesia for routine clinical procedures. The zolazepam:tiletamine (Z:T) ratio was calculated. Peak concentrations occurred at 9-33 min and ranged from 83.5 to 379.2 ng/mL for tiletamine and 301.1 to 1239.3 ng/mL for zolazepam after correction for dose by weight. There were no significant differences between tigers and leopards. The Z:T ratio was generally <5 and did not differ between species. In both tigers and leopards, zolazepam metabolism appeared to be primarily via demethylation. There was evidence for hydroxylation in leopards, but much less in tigers than leopards. No major differences between the species in parent pharmacokinetics were identified. The metabolism of tiletamine could not be defined with any degree of certainty for either species.
Asunto(s)
Anestésicos/farmacocinética , Animales de Zoológico/metabolismo , Panthera/metabolismo , Tigres/metabolismo , Tiletamina/farmacocinética , Zolazepam/farmacocinética , Animales , Cromatografía Líquida de Alta Presión/veterinaria , Combinación de Medicamentos , Femenino , Inyecciones Intramusculares/veterinaria , Cinética , Masculino , Espectrometría de Masas , Especificidad de la EspecieRESUMEN
1. An equal-dose combination of tiletamine and zolazepam (Telazol®) is used as a veterinary anesthetic. There also have been reports of human abuse of Telazol®. The pharmacokinetics and metabolic fate of tiletamine and zolazepam and the rationale for their administration as an equal-dose combination are unclear. 2. The single-dose pharmacokinetics of intramuscular tiletamine and zolazepam (3 mg/kg each) in 16 Yorkshire-crossbred pigs were determined. The metabolites of tiletamine and zolazepam in pig plasma and urine were identified by mass spectrometry. The metabolic stability of tiletamine and zolazepam and the kinetics of formation of their metabolites by pig- and human-liver microsomes were determined. 3. Higher concentrations of zolazepam were observed in pig plasma and it was cleared more slowly compared to tiletamine (apparent clearance: 11 versus 134 l/h; half-life: 2.76 versus 1.97 h). Three metabolites of zolazepam and one metabolite of tiletamine were identified in pig urine, plasma and in microsomal incubations. In vitro formation of each of these metabolites in microsomes was biphasic involving a high-affinity/low-capacity and a low-affinity/high-capacity enzyme. The in vitro metabolic stability of tiletamine was considerably lower compared to zolazepam. 4. These results collectively point to major pharmacokinetic and metabolic differences between the two components of this fixed-dose anesthetic combination.
Asunto(s)
Microsomas Hepáticos/efectos de los fármacos , Tiletamina/administración & dosificación , Tiletamina/farmacocinética , Zolazepam/administración & dosificación , Zolazepam/farmacocinética , Animales , Combinación de Medicamentos , Quimioterapia Combinada/métodos , Humanos , Inyecciones Intramusculares , Masculino , Especificidad de la Especie , Porcinos , Tiletamina/sangre , Tiletamina/orina , Zolazepam/sangre , Zolazepam/orinaRESUMEN
A mixture of tiletamine, a dissociative anesthetic, and zolazepam, a minor tranquilizer, has been widely used as an anesthetic or an immobilizing agent in a variety of animal species. However, interestingly, their pharmacokinetic behaviors have been published only in polar bears and pigs. In this study, we introduce a sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for determining the two drugs in dog plasma. After simple protein precipitation with acetonitrile including midazolam (internal standard), the analytes were chromatographed on a reversed-phase column with a mobile phase of 10 m m ammonium acetate aqueous solution and acetonitrile (1:4, v/v). The accuracy and precision of the assay were in accordance with FDA regulations for the validation of bioanalytical methods. This method was used to measure the concentrations of zolazepam and tiletamine in plasma after a single intramuscular 10 mg dose of each in beagle dogs.
Asunto(s)
Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Tiletamina/sangre , Zolazepam/sangre , Animales , Perros , Estabilidad de Medicamentos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Tiletamina/química , Tiletamina/farmacocinética , Zolazepam/química , Zolazepam/farmacocinéticaAsunto(s)
Anestésicos Disociativos/farmacocinética , Ansiolíticos/farmacocinética , Porcinos/metabolismo , Tiletamina/farmacocinética , Zolazepam/farmacocinética , Anestesia General/veterinaria , Anestésicos Disociativos/administración & dosificación , Anestésicos Disociativos/sangre , Animales , Ansiolíticos/administración & dosificación , Ansiolíticos/sangre , Área Bajo la Curva , Quimioterapia Combinada , Infusiones Intravenosas/veterinaria , Inyecciones Intramusculares/veterinaria , Porcinos/fisiología , Tiletamina/administración & dosificación , Tiletamina/sangre , Zolazepam/administración & dosificación , Zolazepam/sangreRESUMEN
The combination of tiletamine HCl and zolazepam HCl has been used on many species of wild mammals. Short induction time, low dosage, satisfactory safety margins, relatively constant immobilization time, and smooth recovery are benefits reported. This combination (Zoletil 100) was used during a study on behavioural ecology of the crested porcupine (Hystrix cristata) in a Mediterranean coastal area (Maremma Regional Park, Tuscany, Italy). We used this mixture 42 times on 31 individuals. Mean adult dose was (+/- SE) 7.24 +/- 0.37 mg/kg (74.0 +/- 3.0 mg/individual). Average adult induction time was 5.3 min (+/- 1.1) and average adult immobilization time was 22.6 min (+/- 6.0). One adult male porcupine died after chemical restraints. The use of tiletamine-zolazepam seems adequate for chemical immobilization of crested porcupines under field conditions, mainly because of its short induction time, small volume to be injected and wide safety margin.
Asunto(s)
Anestésicos Disociativos , Combinación de Medicamentos , Inmovilización , Roedores/fisiología , Tiletamina , Zolazepam , Anestésicos Disociativos/efectos adversos , Anestésicos Disociativos/farmacocinética , Anestésicos Disociativos/farmacología , Animales , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Seguridad , Tiletamina/efectos adversos , Tiletamina/farmacocinética , Tiletamina/farmacología , Zolazepam/efectos adversos , Zolazepam/farmacocinética , Zolazepam/farmacologíaRESUMEN
A pharmacokinetic and tissue residue study was conducted to assess the risks associated with human consumption of polar bears in arctic Canada that have been exposed to the immobilizing drug Telazol, a mixture of tiletamine hydrochloride and zolazepam hydrochloride. Twenty-two bears were remotely injected with about 10 mg/kg of Telazol. Following immobilization, serum samples were collected serially at regular intervals until the bears awakened. Sixteen of the bears were relocated and killed under permit by local hunters at various times from 0.5 to 11 days after dosing. Serum, kidney, muscle and adipose tissue samples were collected immediately after death. All samples were stored at -70 C until analysis by HPLC. The concentration-time data of tiletamine and zolazepam in serum during the immobilization period were fitted to curves by computer and the pharmacokinetic parameters assessed. In addition, the serum and tissue samples collected at the time of death were analyzed for both parent drugs, for one metabolite of tiletamine (CI-398), and for three metabolites of zolazepam (metabolites 1, 2 and 4). A one-compartment model with first-order absorption and elimination best fit the time-series data for the drugs in serum during the immobilization period. This model gave half-lives (mean +/- SE) for tiletamine and zolazepam of 1.8+/-0.2 h and 1.2+/-0.08 h, respectively, clearance values of 2.1+/-0.3 l x h(-1) x kg(-1) and 1.1+/-0.1 l x h(-1) x kg(-1), and volumes of distribution of 5.2+/-0.6 l/kg and 1.8+/-0.2 l/kg. The concentrations of both drugs and their metabolites declined rapidly to trace levels by 24 h post-dosing, although extremely low concentrations of some metabolites were encountered sporadically over the entire sampling period. In particular, zolazepam metabolite 2, remained detectable in fat and muscle tissue at the end of the study, 11 days after dosing. It was concluded that during immobilization, both tiletamine and zolazepam levels decline rapidly in a monoexponential fashion, and their pharmacokinetic parameters in polar bears are similar to those observed in other species. Tissue levels of the drugs and their metabolites declined sufficiently rapidly that individuals eating meat from exposed bears would be unlikely to experience pharmacological effects from the drugs. Nevertheless, slight exposure to the drugs and/or their metabolites might be possible for an indeterminate time after dosing.