The following observations relevant to systemic absorption were made in clinical studies. In one uncontrolled study a statistically significant decrease in responsiveness to metyrapone was noted in 15 adult steroid-independent patients treated with mg of flunisolide per day (the maximum recommended dose) for 3 months. A small but statistically significant drop in eosinophils from % to % of total circulating leucocytes was noted in another study in children who were not taking oral corticosteroids simultaneously. A 5% incidence of menstrual disturbances was reported during open studies, in which there were no control groups for comparison.
The first isolation and structure identifications of prednisone and prednisolone were done in 1950 by Arthur Nobile .    The first commercially feasible synthesis of prednisone was carried out in 1955 in the laboratories of Schering Corporation, which later became Schering-Plough Corporation , by Arthur Nobile and coworkers.  They discovered that cortisone could be microbiologically oxidized to prednisone by the bacterium Corynebacterium simplex. The same process was used to prepare prednisolone from hydrocortisone .