Interaction of furosemide with serum thyroxine-binding sites: in vivo and in vitro studies and comparison with other inhibitors.

The diuretic furosemide inhibits serum protein binding of T4 in equilibrium dialysis, dextran-charcoal, and competitive ligand binding separation systems and displaces [125I]T4 from isolated preparations of T4-binding globulin (TBG), prealbumin, and albumin. Equilibrium dialysis studies of undiluted normal serum showed that about 10 micrograms/ml furosemide increased the free T4 and free T3 fractions. Displacement occurred at lower drug concentrations in sera with subnormal albumin and TBG levels. Binding of [14C]furosemide to TBG was inhibited by unlabeled T4, suggesting that furosemide and T4 share a common binding site. A single oral dose of 500 mg furosemide given to five patients maintained on peritoneal dialysis increased the percentage of charcoal uptake of [125I]T4 (using serum diluted 1:10) from 4.1 +/- 1.0 (+/- SE) to 10.8 +/- 4.3 (P less than 0.01) after 2 h, while decreasing total T3 from 75 +/- 5 to 56 +/- 13 ng/dl (P less than 0.01) and total T4 from 6.7 +/- 0.9 to 4.8 +/- 0.8 micrograms/dl (P less than 0.01) after 5 h. Various ligands inhibited [125I]T4 binding to serum proteins in the following relative molar relationship: T4, 1; furosemide, 1.5 X 10(3); fenclofenac, 2 X 10(4); mefenamic acid. 2.5 X 10(4); diphenylhydantoin, 4 X 10[4); ethacrynic acid, 10(5); heparin 5 X 10(5); 2-hydroxybenzoylglycine, 10(6); and sodium salicylate, 1.5 X 10(6). These studies demonstrate that furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower total T4 and T3 levels. The drug is much more potent on a molar basis than other drug inhibitors of T4 binding, but at normal therapeutic concentrations, furosemide is unlikely to decrease serum T4 or T3. However, high doses, diminished renal clearance, hypoalbuminemia, and low TBG accentuate its T4- and T3-lowering effect. Hence, furosemide should be considered a possible cause of low thyroid hormone levels in patients with critical illness. The significance of this drug in reports of impaired hormone and drug binding in renal failure requires further assessment.

Influence of urinary sodium on calcium excretion in normal individuals. A redefinition of hypercalciuria.

The twenty-four hour urinary excretion of calcium and sodium was measured in 38 normal volunteers after a week on a diet containing 400 mg of calcium per day. There was a significant correlation (P less than 0.001) between calcium and sodium excretion. The normal range of calcium excretion as a function of sodium excretion has been determined. This approach sharpens the definition of hypercalciuria by taking into account the influence of dietary sodium intake. It also removes the necessity of regulating dietary sodium as well as calcium intake before measuring calcium excretion in patients who form recurrent renal stones.

Metronidazole pharmacokinetics in patients with acute renal failure.

The pharmacokinetics and metabolism of intravenous metronidazole were studied in six patients with acute renal failure. In two of the patients a single dose (500 mg) of metronidazole was administered, whereas in four patients the steady-state pharmacokinetics were studied after four days therapy of 500 mg twice daily. Plasma concentrations of metronidazole and its hydroxy and acetic acid metabolites were measured by a specific and sensitive HPLC method. The volume of distribution was 0.65 +/- 0.13 l/kg (mean +/- S.D.), elimination half-life was 9.9 +/- 2.5 h and total plasma clearance was 55.5 +/- 17.7 ml/min. Renal clearance was almost non-existent (1.4 +/- 1.4 ml/min), whereas non-renal clearance was 54.0 +/- 18.2 ml/min. Steady-state plasma concentrations of metronidazole were 15.3 +/- 3.8 mg/l, the hydroxy metabolite were 17.4 +/- 2.0 mg/l and the acetic acid metabolite were 1.2 +/- 0.8 mg/l. In the patients studied, a dosing regimen of 500 mg twice daily resulted in therapeutically adequate blood levels of metronidazole.

Management of quinine toxicity.

The clinical findings, investigations, and course of three patients who ingested quinine sulphate or bisulphate tablets and suffered severe visual loss are described. Methods and control of treatment for these patients are discussed, and the assessment of the effectiveness of treatment, and its relationship to the visual outcome are considered.

Elimination of amphotericin B in impaired renal function.

The influence of impaired renal function on the steady-state plasma clearance of amphotericin B was determined in seven patients with creatinine clearances ranging from zero to normal. Contrary to previous reports, steady-state plasma concentrations of total drug were lower in uremic patients than in patients with normal renal function. Total plasma clearance of amphotericin B ranged from 16.7 to 39.9 ml/min, correlated directly with the plasma creatinine concentration, and correlated inversely with the creatinine clearance. Urinary excretion of unchanged drug accounted for less than 10% of the dose. In 10 healthy subjects, mean percent of amphotericin B unbound in plasma was 3.55 +/- 0.32 (SD). Binding was determined in a further group of 10 uremic patients. Mean unbound percent (4.15 +/- 0.73, SD) was higher than in the healthy subjects, and the binding ratio (molar concentration of bound to unbound drug) correlated weakly with the creatinine clearance. This suggests that plasma clearance of unbound amphotericin B and, therefore, steady-state plasma concentrations of unbound drug are not affected by renal impairment, and that dosage requirements will be overestimated if based on measurements of total drug plasma concentration.

Disposition and removal of metronidazole in patients undergoing haemodialysis.

The pharmacokinetics and haemodialysis clearance of metronidazole were investigated in four renal failure patients after a single 500 mg intravenous dose and in two renal failure patients on continuous treatment with metronidazole. During dialysis, the volume of distribution of metronidazole was 0.60 +/- 0.04 l/kg, total clearance was 196.0 +/- 60.6 ml/min and the elimination half-life had an harmonic mean of 2.14 h. Extraction across the dialyser was 51.5 +/- 7.8% and was limited to the distribution of drug in plasma water. Dialysis clearance was 125.0 +/- 32.7 ml/min, which represented 62 +/- 6% of total clearance and was 1.75 times the sum of the other clearance mechanisms. The hydroxy metabolite was extracted and cleared by the dialyser to the same degree as metronidazole itself. During the 4 h-dialysis 44.9 +/- 2.6% of the dose was removed by the dialyser in the four patients administered a single dose. Metronidazole is efficiently cleared and extensively removed by dialysis, and therefore dosage adjustments and alterations in the timing of dosage administration are essential in patients undergoing haemodialysis.

Hemodialysis, peritoneal dialysis, plasmapheresis and forced diuresis for the treatment of quinine overdose.

Peritoneal dialysis, hemodialysis, plasma exchange and forced diuresis have been reported to accelerate removal of quinine following quinine poisoning. All these modalities were used simultaneously to treat a 19 year old youth who had become blind as a result of an overdose of quinine tablets. The serum quinine level was measured at 10.5 microgram/ml 13 hours after quinine ingestion. Forced diuresis accounted for the removal of 557 mg of quinine in the first 5 hours and a total of 1625 mg over 75 hours., A 6 hour hemodialysis recovered 30 mg of quinine while peritoneal dialysis removed an average of 1.6 mg/hr over the first 48 hours. Plasmapheresis over 3 hours exchanged 2 liters of plasma containing a total of 8.5 mg of quinine. Some vision returned 19 hours after quinine ingestion but did not become normal until 5 1/2 months later. We conclude that, hemodialysis, peritoneal dialysis and plasma exchange made only a minor contribution to quinine elimination by comparison with renal excretion of quinine.

The measurement of glomerular blood flow in the rat kidney: influence of microsphere size.

1. Radioactively labelled microspheres were used to determine glomerular blood flow in glomerular populations with distinct vascular characteristics. Two batches of microspheres (15 +/- 5.0 micrometer diameter and 7.0--10 micrometer diameter) were utilized. 2. The results show that the larger microspheres overestimate the superficial glomerular blood flow (414 +/- 61 nl/min, mean +/- s.e.m.) and underestimate the deep glomerular blood flow (98 +/- 10 nl/min), when compared with the data obtained with 7.0--10 micrometer diameter microspheres (317 +/- 30 nl/min and 209 +/- 23 nl/min, respectively). 3. The rheological artefact associated with the use of larger microspheres is confirmed by finding an uneven size distribution of microspheres lodged in the glomeruli. In each of three experiments, the mean diameter of 200 microspheres lodged in the superficial glomeruli (16.43 +/- 0.27 micrometer, 15.87 +/- 0.23 micrometer and 16.58 +/- 0.27 micrometer) was significantly greater than that found in the deep glomeruli (15.36 +/- 0.15 micrometer, 15.25 +/- 0.21 micrometer and 15.73 +/- 0.24 micrometer; P less than 0.01, less than 0.05 and less than 0.01, respectively). No such difference was detected when the 7.0--10 micrometer spheres were used. 4. Glomerular blood flow can be measured at all depths of the rat's cortex and the demonstrated rheological artefact associated with use of the larger spheres is circumvented with the use of 7.0--10 micrometer microspheres.

Permanent hypertension after renal homotransplantation in man.

1. In forty-one patients who underwent renal homotransplantation the following measurements were made: (a) blood flow and its distribution in the transplanted kidney as measured by the 85-Kr washout method; (b) renin release in the renal vein of the transplant; (c) arteriovenous difference in plasma renin activity (PRA) of the recipient's remaining left kidney. 2. Eleven transplanted patients were normotensive. Renal haemodynamic data were comparable with those obtained in potential kidney donors. 3. Three hypertensive patients had chronic rejection. The mean renal blood flow and the percentage flow in the first component of the washout curve were reduced. Renin release from the transplant, however, was normal. 4. Ten hypertensive patients had transplant artery stenosis. In eight of them renin release from the grafts as well as peripheral PRA were within normal range. This result is similar to experimental data obtained in Goldblatt renovascular hypertension. The two patients with the tightest artery stenosis had an elevated renin release from the transplant. 5. Thirteen hypertensive patients had elevated arteriovenous difference in PRA of the recipient's own left kidney. Peripheral PRA was significantly higher than in normotensive patients. Left nephrectomy relieved hypertension in ten of them; three have not so far undergone nephrectomy. 6. In four other cases hypertension was also relieved by removal of the patient's own kidney; however, the arteriovenous difference in PRA of that kidney fell within normal range.

Osmotic Nephrosis Induced by Water-Soluble Triiodinated Contrast Media in Man. A Retrospective Study of 47 Cases.

Renal biopsies were performed in 211 patients which 10 days of excretory urography or renal arteriogrpahy in which diatrizoate, iothalamate or ioxithalamate had been used. In 47 renal specimens, osmotic nephrosis of the proximal tubular cells was found. Previous renal function had been normal in 10 patients, moderately impaired in 19, and severely impaired in 18. Tubular atrophy and/or necrosis was associated with histological features in 29 of 47 patients. Diffuse osmotic nephrosis was more often found in patients biopsied soon after roentgenography and also with severe renal insufficiency, but was not necessarily associated with declining renal function. The mechanism(s) by which contrast media may induce osmotic nephrosis remains unclear.