Albert W. Pruitt

Furosemide binding to human albumin and plasma of nephrotic children.

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° C and pH 7.4 with 14C‐F. At a total concentration of 3.4 µ/ml (therapeutic range), the unbound fraction of F to 4 gm per 100 ml HA was 2.79 ± 0.35. The degree of binding was relatively constant from 1.8 to 36 µ/ml of F concentration. The percentage of unbound F doubled when total concentration of the drug was increased more than 130 times 0.8 to 245 µ/ml). F has two classes of binding sites (n1 = 1.42, k1 = 5.07 × 104 M−1; n2 = 3.4. k2 = 1.58 × 104 M−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 µ/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.

Effects of Maintenance Digoxin Therapy on Systolic Time Intervals and Serum Digoxin Concentrations

Systolic 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 (PEP1) and PEP/left ventricular ejection time (LVET). After the thirteenth dose of 0.25 mg/day there was significant shortening of PEP1 and PEP/LVET. Shortening of QS2i correlated significantly with SDC 24 hours after the thirteenth dose of 0.5 mg. These data suggest that after 13 days of treatment with 0.25 and 0.5 mg/day of digoxin, a positive inotropic effect occurs as reflected by STI shortening. A greater effect was recorded with the 0.5 mg dose.

Pulmonary effects of furosemide in preterm infants with lung disease

Twenty preterm infants recovering from respiratory distress syndrome at 1 week of age were randomized in this study either to a control or a treatment group. Those treated received a single daily dose of furosemide (1 mg/kg) intravenously. Pulmonary compliance was observed to improve significantly at two hours in the treated group, as compared with that in the controls. The calculated alveolar-arterial oxygen gradient was noted to decrease two hours after furosemide and to remain decreased over the four-day period in the treated group. This improvement in lung function was not secondary to diuresis in the infants treated with furosemide. We conclude that furosemide may have a direct pulmonary effect and improve lung function acutely as well as with chronic administration.

Depression of renal clearance of furosemide in man by azotemia.

The renal clearance of furosemide and tetraethylammonium (TEA) were compared in 10 patients with hypertensive nephropathy. BUN and creatinine ranges were 10 to 88 mg/dl and 0.9 to 3.8 mg/dl, respectively. Diuretics were discontinued 48 hr prior to the study, and 2 consecutive clearances (ml/min/1.73 m2BSA) of creatinine were performed. The patient then received a bolus followed by a constant infusion of furosemide‐14C and tetraethylammonium‐14C (analyzed by specijic methodology for plasma and urine), both in subpharmacologic doses. After 40‐min equilibration sequential 20‐min clearance periods were obtained. Both the clearance of furosemide (range 17 to 133) and TEA (range 99 to 443) correlated negatively with BUN and serum creatinine and positively with creatinine and urea clearances. Thus, by using a constant‐infusion technique we demonstrated that the renal clearance of furosemide is depressed by azotemia in man and that there was greater depression with furosemide than with TEA.

Variations in the fate of triamterene

Triamterene is a pteridine used therapeutically as a diuretic. In order to better understand variations in effect and toxicity of triamterene in individuals, the fate of the drug in man was investigated. Both nonradioactive and 14C‐labeled forms of the drug were administered, and specific methods of analysis were used to separate the parent compoundJrom its metabolite. Individual variation in absorption, binding, and elimination was noted. The drug was excreted in bile as well as urine. Rapid and extensive metabolism of the agent occurred after oral and intravenous doses in healthy adult men. The peak plasma levels of the drug after an oral dose (200 mg) were under 0.3 µg/ml, but the concentration of the primary metabolite (2,4,7‐triamino‐6‐p‐hydroxyphenylpteridine) was higher. The urinary excretion of the metabolite was at least three times that of the parent drug.

Management of clonidine ingestion in children.

Six cases of toxic ingestion of clonidine hydrochloride are reviewed. Apnea, respiratory depression, and rhythm disturbances were more frequent in our patients than in those previously reported; hypotension and bradycardia occurred at a similar frequency. Satisfactory management consisted of close attention to vital signs and judicious treatment of specific physiologic abnormalities. Atropine effectively corrected bradycardia. Tolazoline was found to be ineffective in reversing symptoms and signs of clonidine overdosage. Hypotension was managed by volume expansion, and if necessary, by a continuous infusion of dopamine. Naloxone, although not used in our patients, may be of both diagnostic and therapeutic value in treating clonidine overdosage.

Hypertension, hyperreninemia and a solitary renal cyst in an adolescent.

Solitary renal cysts associated with hypertension and documented hyperreninemia are relatively uncommon. A 13 year old boy with these findings is described (pressure 160/120 mm Hg). Contrast studies of the urinary tract and arteriography with selective renal vein sampling demonstrated a solitary cyst in the right kidney. The ratio of plasma renin activity in the right renal vein to left renal vein (RRV:LRV) was 2.35:1. After drainage of the cyst, there was a marked reduction in both systolic and diastolic pressures (126/84 mm Hg). Hypertension has not recurred during 14 months follow-up.

Cyclic GMP-dependent and cyclic AMP-dependent protein kinases, protein kinase modulators and phosphodieterases in arteries and veins of dogs Distribution and effects of arteriovenous fistula and arterial occlusion

Possible involvement of cyclic GMP-dependent and cyclic AMP-dependent protein kinases, protein kinase modulators and cyclic nucleotide phosphodiesterases in functions of vascular tissues were investigated in the dog. All of the above activities, localized in the smooth muscle-rich inner layer of the blood vessels, were found to be higher in the arteries than in the veins. The peripheral arteries were disproportionately richer in cyclic GMP-dependent protein kinase (as indicated by high ratios of cyclic GMP-dependent to cyclic AMP-dependent protein kinase) than were the veins, with the exception of the pulmonary artery, an atypical arterial tissue exposed to low blood pressure. Interestingly, the protein kinase ratio for the aorta, an artery with no significant role in blood pressure regulation, was not higher than that for the vena cava. Creation of femoral arteriovenous fistulae in the dogs led to preferential reductions in the cyclic GMP-dependent enzyme activity both in the proximal and distal arteries, whereas it was elevated in the stressed vein distal to the anastomotic site. The cyclic GMP-dependent enzyme was preferentially reduced in the saphenous artery distal to occlusion. Changes in the cyclic GMP-dependent enzyme activity appeared to precede gross atrophy or hypertrophy of the vessels. It is suggested that the vascular cyclic GMP-dependent protein kinase may be closely related to peripheral resistance and its regulation.

Diuretic effect of furosemide in acute glomerulonephritis

Twenty-five children with the diagnosis of acute glomerulonephritis were treated with oral or intravenous doses of furosemide. The intravenous administration of 1 mg/kg or greater resulted in an increase in urine volume in all patients. Oral doses of less than 2 mg/kg were not as effective, but there was wide variation in diuretic response to the drug. In 13 patients, plasma concentrations of furosemide were measured. The plasma half-life varied from 2.3 to 4.4 hours after intravenous administration of the drug. The plasma concentration of furosemide did not correlate with diuretic response.

Pharmacologic approach to the management of childhood hypertension.

Management of mildly elevated blood pressures may not require drug therapy, but pharmacologic agents are usually needed to control greater elevations. Antihypertensive agents are reviewed in terms of sites of action. Knowledge of site of action is particularly crucial for the patient who requires multiple agents, and helps the physician to choose agents with complementary effects and different sites of action.