Efficacy of aerosolized methylprednisolone in an animal model of aspiration pneumonitis.

Methylprednisolone (MPSS, 30 mg/kg) was administered intrabronchially by nebulization 15 min after HCl aspiration in anesthetized dogs. Control animals (SALINE group) received saline nebulization without steroid. Hemodynamic and oxygenation variables were determined before and 1, 2 and 3 hr after aspiration. At autopsy, lungs were removed and desiccated for gravimetric determination of lung water. Three hr postaspiration, intrapulmonary shunting (Qsp/Qt) in the MPSS group was significantly lower (22 vs 41%) and arterial oxygen tension (PaO2) was higher (265 vs 122 torr) than in the SALINE group. Thus, direct application of this glucocorticoid to airway membranes following acid aspiration improved gas exchange without obvious benefit to edema formation or cardiac output.

Steroid-protein interactions. Human corticosteroid binding globulin: some physicochemical properties and binding specificity.

Reducing agents (dithiothreitol and beta-mercaptoethanol) significantly decrease the affinity constants of the human corticosteroid-binding globulin (CBG)-cortisol complex in proportion to their concentration; the resulting Ka values are more consistent than those obtained in the absence of the reductants. The effect is reversible. The equilibrium association constants of the CBG complexes with cortisol and progesterone show a relatively broad pH maximum between pH 8 and 11. In this pH range, cortisol was found to be bound more strongly than progesterone; this relationship is reversed around pH 6. The van't Hoff plot of the temperature effect on Ka of the CBG-cortisol complex (4-41 degrees C) exhibits a nonlinear, possibly biphasic temperature dependency. The shape of the van't Hoff plot was similar in the presence of mercaptoethanol. The association of cortisol and progesterone to human CBG at 4 and 37 degrees C is enthalpy driven, compensating for the unfavorable change in entropy. Studies with 47 steroids served to elucidate the influence on binding affinity of polar and nonpolar groups and other structural alterations. The contribution of specific structural changes in the steroid molecule to the free energy of binding can be calculated from the results. Important structures for optimal binding are the 20-oxo group, a 10 beta-methyl group, and a double bond at the 4 position. A complementary image of the binding site with respect to the nature of binding at various locations is proposed.