The extent and nature of furosemide (F) binding to human albumin (HA) and to the plasma of 6 children with nephrotic syndrome were studied by equilibrium dialysis at 37 degrees C and pH 7.4 with 14C-F. At a total concentration of 3.4 mug/ml (therapeutic range), the unbound fraction of F to 4 gm per 100 ml HA was 2.79 plus or minus 0.35. The degree of binding was relatively constant from 1.8 to 36 mug/ml of F concentration. The percentage of unbound F doubled when total concentration of the drug was increased more than 130 times (1.8 to 245 mug/ml). F has two classes of binding sites (n1 = 1.42, k1 = 5.07 times 10-4 M-minus 1; n2 = 3.4, k2 = 1.58 times 10-4 M-minus 1); interaction with HA involves hydrophobic, ionic, and hydrogen forces. Acetylsalicylic acid (ASA), acetazolamide, diazoxide, phenylbutazone, sulfisoxazole (S), and tolbutamide (T) decreased F binding. Combinations of ASA, S, and T exerted a strong additive displacing effect. The binding of the F metabolite (4-chloro-5-sulfamoylanthranilic acid, CSA) was studied at 1.3 and 2.6 mug/ml. The unbound fraction was 5 times that of F. CSA did not influence F binding. Studies with plasma of 7 healthy adults showed that albumin is the only plasma protein responsible for F binding. The plasma albumin concentration range of the children with nephrotic syndrome was 0.6 to 2.1 gm per 100 ml. There was some correlation between albumin concentration and binding of F (2.8 to 9.6% unbound); this corresponded with findings with HA. Albumin concentrations lower than 2 gm per 100 ml seemed to influence the extent of the unbound fraction of F considerably.

No abstract

Pharmacokinetic studies in 4 children with hypo glycemia who required diazoxide therapy revealed a half‐life of the drug in blood of 9.5 to 24 hmlrs. The blood level of diazoxide in these children while receiving maintenance therapy was 15 to 50 p.g per milliliter. Hyperglycemia and acidosis developed in one of these patients in the presence of a persistent blood level above 100 ug per milliliter. Twenty‐four hour urinary excretion of unchanged drug in 2 patients was 20 and 33 per cent of the initial dose, and 80 per cent in one patient on maintenance. In order to investigate the fate of the drug better, 3H‐diazoxide was purified for use in adult volunteers and animals. The half‐life of the drug in plasma of 2 adults was 24 and 36 hours. In these subiects as much as 94 per cent of the radioactive dose was recovered in the urine. About half the radioactivity in urine was present as unchanged drug. The plasma half‐life of 3H‐diazoxide in rats and dogs was much shorter than in man.

SUMMARYSystolic time intervals (STI) and serum digoxin concentrations (SDC) were measured in eight patients with compensated atherosclerotic and/or hypertensive heart disease who received oral digoxin 0.25 mg/day or 0.5 mg/day for alternate two-week periods without a loading dose. Control data were obtained both before and after the four weeks of treatment. After 13 days treatment with digoxin, 0.5 mg/day, there was a significant decrease in total electromechanical systole corrected for heart rate (QS2i), pre-ejection period (PEP), pre-ejection period corrected for heart rate (PEP,) Methods Eight patients, all in normal sinus rhythm, with compensated atherosclerotic and/or hypertensive heart disease were studied. Four patients were male and four patients were female. Ages ranged from 35 years to 68 years. Five patients were receiving maintenance doses of digoxin, orally, at the time of selection for the study. Digoxin was discontinued at least two weeks prior to the first control observation. In all patients, SDC at the time of the first control observation was less than 0.4 ng/ml. Diuretics, antihypertensive agents, and sedatives were continued in unchanged doses. Patients taking diuretics received supplemental oral potassium chloride. The purpose of the study was fully explained to each patient and written informed consent was obtained.The initial evaluation of each patient included determinations of blood urea nitrogen, serum creatinine, sodium, potassium, chloride, carbon dioxide combining power, calcium, carotene, and thyroxine. The results of these studies were all within the normal range. Chest X-rays and 12-lead electrocardiograms were compatible with the clinical diagnoses.Two sets of control observations (Cl and C2) were obtained two weeks before starting digoxin. Four of the patients then received digoxin 0.25 mg/day for two weeks