RESUMEN
BACKGROUND: The highly selective α2 -adrenoreceptor agonist, dexmedetomidine, exerts neuroprotective, analgesic, anti-inflammatory and sympatholytic properties that may be beneficial for perinatal asphyxia. The optimal safe dose for pre-clinical newborn neuroprotection studies is unknown. METHODS: Following cerebral hypoxia-ischaemia, dexmedetomidine was administered to nine newborn piglets in a de-escalation dose study in combination with hypothermia (whole body cooling to 33.5°C). Dexmedetomidine was administered with a loading dose of 1 µg/kg and maintenance infusion at doses from 10 to 0.6 µg/kg/h. One additional piglet was not subjected to hypoxia-ischaemia. Blood for pharmacokinetic analysis was sampled pre-insult and frequently post-insult. A one-compartment linear disposition model was used to fit data. Population parameter estimates were obtained using non-linear mixed effects modelling. RESULTS: All dexmedetomidine infusion regimens led to plasma concentrations above those associated with sedation in neonates and children (0.4-0.8 µg/l). Seven out of the nine piglets with hypoxia-ischaemia experienced periods of bradycardia, hypotension, hypertension and cardiac arrest; all haemodynamic adverse events occurred in piglets with plasma concentrations greater than 1 µg/l. Dexmedetomidine clearance was 0.126 l/kg/h [coefficient of variation (CV) 46.6.%] and volume of distribution was 3.37 l/kg (CV 191%). Dexmedetomidine clearance was reduced by 32.7% at a temperature of 33.5°C. Dexmedetomidine clearance was reduced by 55.8% following hypoxia-ischaemia. CONCLUSIONS: Dexmedetomidine clearance was reduced almost tenfold compared with adult values in the newborn piglet following hypoxic-ischaemic brain injury and subsequent therapeutic hypothermia. Reduced clearance was related to cumulative effects of both hypothermia and exposure to hypoxia. High plasma levels of dexmedetomidine were associated with major cardiovascular complications.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2/farmacocinética , Asfixia Neonatal/complicaciones , Dexmedetomidina/farmacocinética , Hipotermia Inducida , Hipoxia-Isquemia Encefálica/tratamiento farmacológico , Fármacos Neuroprotectores/farmacocinética , Agonistas de Receptores Adrenérgicos alfa 2/sangre , Agonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Animales , Dexmedetomidina/sangre , Dexmedetomidina/uso terapéutico , Modelos Animales de Enfermedad , Hipoxia-Isquemia Encefálica/etiología , Masculino , Tasa de Depuración Metabólica , Fármacos Neuroprotectores/sangre , Fármacos Neuroprotectores/uso terapéutico , Dinámicas no Lineales , Sus scrofa , PorcinosRESUMEN
Aspects of the metabolism and health of 63 cows which had been treated with different amounts of bovine somatotrophin (BST) daily in the preceding lactation and 25 control cows were studied. The aims of the study were first, to identify cows with ketotic conditions, either by measurements of blood metabolite concentrations or by clinical observations, secondly, to evaluate the risk of such conditions in cows treated with BST in the preceding lactation, and thirdly, to examine the metabolic and production consequences of the ketotic conditions in an environment in which the cows' health, body condition and nutrition were closely observed. The cows were categorised objectively by the use of cluster analysis into non-ketotic cows and ketonaemic cows, on the basis of their plasma metabolite concentrations. Twelve of the control cows and none of the cows previously treated with BST were classified as ketonaemic. Similarly, nine of the control cows but only two of the cows previously treated with BST had clinical ketosis. Some, but not all, of the decrease in the risk of clinical ketosis was attributable to the lower body condition score of the cows previously treated with BST. The clinically ketotic cows had a greater risk of other illness in the first 10 days post partum than their herdmates, but the ketonaemic cows had a significantly lower risk of other disease in the first 10 days post partum. The ketonaemic control cows were significantly heavier than the non-ketotic control cows, but they maintained a higher dry matter intake than the latter cows, probably a key factor in reducing the risk of clinical ketosis.
Asunto(s)
Enfermedades de los Bovinos , Hormona del Crecimiento/farmacología , Estado de Salud , Cetosis/veterinaria , Lactancia/efectos de los fármacos , Ácido 3-Hidroxibutírico , Envejecimiento/fisiología , Análisis de Varianza , Animales , Glucemia/análisis , Peso Corporal/efectos de los fármacos , Bovinos , Colesterol/sangre , Análisis por Conglomerados , Relación Dosis-Respuesta a Droga , Ácidos Grasos no Esterificados/sangre , Femenino , Hidroxibutiratos/sangre , Cetosis/epidemiología , Lactosa/análisis , Leche/química , Leche/metabolismo , Factores de Riesgo , Factores de TiempoRESUMEN
Metabolic and production responses are reported for 72 cows treated with bovine somatotropin (BST) for 30 days starting at day 70 of lactation. Of these 72 cows, 48 had been exposed in the preceding lactation to long-term treatment with BST at 3 dosages and 24 (controls) had not been given BST. Approximately half of the cows in each group were parity-2 cows, the rest were older. Comparisons between groups were made separately for parity-2, and older cows. Analyses, using pretreatment values of each variable as a covariate, indicated that older cows, but not parity-2 cows, significantly (P less than 0.05) increased milk production during treatment. Parity-2 cows, however, had a significantly higher milk fat percentage than controls following treatment. Cows treated with 51.6 or 86 mg BST/d in both parity groups had significantly higher serum-free fatty acids than controls. Estimated net energy balances were significantly lower for older treated cows, but did not significantly differ from controls for parity-2 treated cows. Older cows in the 86 mg of BST/d group tended to have higher concentrations of blood glucose than did older control-group cows. Treatment with BST did not significantly increase serum ketone concentrations in any group of animals, and none of the cows developed clinical ketosis during this period. Estimated net energy balance (ENEB) during treatment was a significant (P less than 0.05) covariate for free fatty acid concentrations in older cows and for milk fat percentage in parity-2 cows. Covariate adjusted analyses, using ENEB during treatment as a covariate, indicated that lipolytic stimuli already acting may be enhanced by treatment with BST, but a negative energy balance was not a necessary precondition for free fatty acid concentrations to increase following somatotropin treatment. Similarly, milk fat percentages for parity-2 treated cows were significantly (P less than 0.05) higher during treatment than controls when ENEB during treatment was used as a covariate. Increased milk fat concentrations in parity-2 treated cows were not associated with significant increases in the ratio of C18:C4-10 milk fatty acids, indicating that increased milk fat resulted from either an increase in incorporation of C18 fatty acids into milk fat coupled with an increase in de novo mammary synthesis of C4-10 milk fatty acids or an increase in C12-16 fatty acids that may arise either from increased tissue mobilization, from diet, or from de novo mammary synthesis.