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1.
J Pept Res ; 49(6): 527-37, 1997 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-9266480

RESUMEN

In the present study, human growth hormone-releasing factor (hGRF) and analogs were successfully pegylated at the carboxy-terminus using a novel solid- and solution-phase strategy. Following synthesis, these pegylated hGRF analogs were evaluated for in vitro and in vivo biological activity. Specifically, hGRF (1-29)-NH2, [Ala15]-hGRF (1-29)-NH2, [desNH2Tyr1, D-Ala2, Ala15]-hGRF(1-29)-NH2 and [His1, Val2, Gln8, Ala15, Leu27]-hGRF(1-32)-OH were each C-terminally extended using a Gly-Gly-Cys-NH2 spacer (previously demonstrated not to alter intrinsic biological activity), and then monopegylated via coupling to an activated dithiopyridyl-PEG reagent. PEG moieties of 750, 2000, 5000 or 10,000 molecular weight (MW) were examined to determine the effect of polymer weight on activity. Initial biological evaluations in vitro revealed that all C-terminally pegylated hGRF analogs retained high growth hormone (GH)-releasing potencies, regardless of the MW of PEG polymer employed. Two of these pegylated hGRF analogs, [desNH2Tyr1, D-Ala2, Ala15]-hGRF (1-29)-Gly-Gly-Cys(NH2)-S-Nle-PEG5000 and [His1, Val2, Gln8, Ala15, Leu27]-hGRF(1-32)-Gly-Cys(NH2)-S-Nle-PEG5000, were subsequently evaluated in both pig and mouse models and found to be highly potent (in vivo potency range = 12-55-fold that of native hGRF). Relative to their non-pegylated counterparts, these two pegylated hGRF analogs exhibited enhanced duration of activity.


Asunto(s)
Hormona Liberadora de Hormona del Crecimiento/farmacología , Polietilenglicoles/química , Animales , Cromatografía Líquida de Alta Presión , Femenino , Hormona Liberadora de Hormona del Crecimiento/análogos & derivados , Humanos , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Adenohipófisis/citología , Adenohipófisis/efectos de los fármacos , Conformación Proteica , Ratas , Ratas Sprague-Dawley , Espectrometría de Masa Bombardeada por Átomos Veloces , Porcinos
2.
Am J Vet Res ; 42(3): 456-61, 1981 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-7271010

RESUMEN

Lasalocid was given to horses in a series of sequentially increasing single oral doses ranging between 5 and 30 mg/kg of body weight, with an appropriate washout period between treatments. One of the 5 horses died after a dosage of 15 mg/kg, 1 of 3 horses died after 21 mg/kg, 1 of 3 horses died after 22 mg/kg, and 1 of 2 horses died after 26 mg/kg. The LD50 of lasalocid for horses was estimated to be 21.5 mg/kg. Monensin was given to horses in a similar manner at dosages of 1, 2, and 3 mg/kg of body weight. One of the 2 horses died after a dosage of 2 mg/kg and 1 horse died after a dosage of 3 mg/kg. The clinical signs of toxicosis observed in horses given either drug were progressive and included depression, ataxia, paresis, and paralysis with partial anorexia. Intermittent profuse sweating was observed before death in horses given monensin.


Asunto(s)
Enfermedades de los Caballos/inducido químicamente , Lasalocido/toxicidad , Administración Oral , Animales , Calcio/sangre , Femenino , Enfermedades de los Caballos/sangre , Enfermedades de los Caballos/patología , Caballos , Riñón/patología , Lasalocido/administración & dosificación , Dosificación Letal Mediana , Hígado/patología , Masculino
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