Laragh and his co-workers1 have demonstrated that chlorothiazide administered to normal subjects in the midst of a sustained water diuresis provokes a flow of urine of substantially higher concentration for a given rate of total osmolar output than urine formed by water-loaded subjects to whom meralluride is given. They suggested that the site of action of chlorothiazide was in the distal portion of the nephron. Here the drug inhibited the production of "free water" which normally results from selective reabsorption of sodium and accompanying anions. A drug acting to interfere with free-water formation would be of therapeutic value to the patient with diabetes insipidus, particularly the nephrogenic type, if attendant losses of electrolytes in the urine were not unduly large.
Crawford and Kennedy2 showed that orally administered chlorothiazide drugs decreased urine volume and doubled osmolality in rats with experimental diabetes insipidus. The effect described for the rats, according
CHLOROTHIAZIDE DERIVATIVES FOR DIABETES INSIPIDUS. JAMA. 1961;178(5):502. doi:10.1001/jama.1961.03040440054012