Biomedical subjects
Publications and source records attributed to G R Aronoff.
The nephrotoxicity of ceftazidime compared with that of cefazolin or cephaloridine and the capacity of ceftazidime to enhance the nephrotoxicity of tobramycin were evaluated in rats. Only cephaloridine and tobramycin given alone altered creatinine clearance or caused significant histological injury. Our data suggest that ceftazidime is no more nephrotoxic than cefazolin and does not enhance the nephrotoxicity of tobramycin.
The study of diabetic nephropathy in experimental animals generally relies on the chemical induction of the diabetic state. Streptozotocin is commonly employed to that end; however, streptozotocin has an inherent nephrotoxic potential. We studied the effects of both streptozotocin, and diabetes on the kidneys of rats given streptozotocin 60 mg/kg, which was sufficient to induce severe diabetes. Our studies, which utilized both transmission and scanning electron microscopy, considered the pharmacokinetics of streptozotocin in renal tissue, as well as the effect of insulin treatment. Renal tissue kinetics were altered by occluding the renal hilum of one kidney during, and for 5 min after, the administration of streptozotocin. We found that, in contrast to alloxan, streptozotocin caused no detectable renal injury at the dose employed. Previously described renal epithelial papillomas were identified, and were not influenced by altering the renal tissue kinetics of the drug. We conclude that no 'protection' procedure is necessary for the kidney when the streptozotocin model of diabetes is employed. In this regard streptozotocin may have greater utility than alloxan.
To determine the effect of decreased renal function on the elimination kinetics of the calcium entry blocker nitrendipine and its metabolite, we gave 18 subjects with various levels of renal dysfunction a single 20-mg oral dose of nitrendipine. Plasma nitrendipine and metabolite concentrations were measured by high performance liquid chromatography 15 times over 48 h after the dose. A compartment-independent pharmacokinetic analysis showed no difference in the absorption, elimination, or metabolism of nitrendipine between subjects with normal renal function and those with impaired renal function. We conclude that renal insufficiency does not alter nitrendipine kinetics.
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The effect of drug dose on piperacillin elimination kinetics was examined in 27 adult subjects with varying renal function. Piperacillin, 15 mg/kg or 60 mg/kg, was given by bolus intravenous injection. The elimination half-life (t1/2) increased five-fold and plasma clearance (Clp) decreased by 80% in patients with renal failure. Both parameters were dose dependent in patients with normal renal function, but not in patients with renal insufficiency. Piperacillin dose dependent elimination is due primarily to capacity limited renal excretion.
In order to formulate a thoughtful and rational approach to drug dosing in renal failure, the nephrologist must consider several features that influence drug disposition in uremia. Drug bioavailability is generally adversely influenced in patients with renal disease. Drug distribution is frequently altered to an unpredictable degree. Drug protein binding is affected not only by changes in the amount of circulating binding protein but also by the accumulation of endogenous toxins. Renal failure frequently affects drug biotransformation. Drug-dosing tables and nomograms are important; however, they are not a substitute for an encompassing clinical approach and sound clinical judgment.
To establish therapeutic guidelines for the use of antibiotics in patients receiving continuous ambulatory peritoneal dialysis (CAPD), we studied the single-dose pharmacokinetics of cefazolin, tobramycin, and vancomycin given intravenously (IV) and intraperitoneally (IP) as well as cephalexin given orally. By the IV or oral route, the antibiotics exhibited half-lives similar to those described in nondialysed, functionally anephric patients. CAPD accounted for only a negligible fraction of the total body clearance when the drugs were given by the IV route. However, when given IP, the drugs were promptly absorbed and achieved therapeutic serum concentrations. The kinetic principle of superposition was applied to predict plasma concentrations after repetitive IP dosing. Therapeutic guidelines are provided.
The data base for rational guidelines to safe, efficacious drug prescribing in adults with renal insufficiency are presented in tabular form. Current medical literature was extensively surveyed to provide as much specific information as possible. When information is lacking, however, recommendations are based on pharmacokinetic variables in normal subjects. Nephrotoxicity, important adverse effects, and special considerations in renal patients are noted. Adjustments are suggested for hemodialysis and peritoneal dialysis when appropriate.
To establish elimination kinetics of mezlocillin in patients with hepatic insufficiency, we gave eight normal subjects and four patients with hepatic insufficiency and normal renal function a single 3-gm dose of mezlocillin by intravenous infusion. Subjects with hepatic insufficiency all had serum bilirubins levels of above 3 mg/dl, prothrombin times more than 2 sec longer than control, and creatinine clearances above 60 ml/min. Mezlocillin concentrations were determined by microbiologic assay. Kinetic analysis was by model-independent methods. Elimination half-life was 0.96 hr for subjects with normal liver function and 2.62 hr for patients with hepatic insufficiency. Mean total body clearance for normal subjects was 247 ml/min, while in patients with hepatic insufficiency it was 125.4 ml/min. We conclude that hepatic insufficiency prolongs mezlocillin elimination and suggest that therapeutic guidelines be set up.
To establish therapeutic guidelines for tobramycin use in patients receiving continuous ambulatory peritoneal dialysis (CAPD), we studied tobramycin single-dose kinetics in CAPD patients. Tobramycin was studied after a 1.5-mg/kg dose given either intravenously (TOB-IV) or intraperitoneally (TOB-IP). TOB-IV provided a plasma concentration above 3 mg/l at 12 hr with a t 1/2 of 39.5 hr. When tobramycin was given intraperitoneally, 52% of the dose was absorbed; peak plasma concentrations were only 1.8 mg/l, and the t 1/2 was 35 hr. CAPD accounted for only 15% to 20% of total body clearance in both groups. The kinetic principle of superposition was used to predict plasma concentrations after repeated TOB-IP. A model using once-a-day dosing predicted that a loading dose of 4 mg/kg followed by 1.5 mg/kg would achieve steady-state plasma concentrations of 2.8 to 4.2 mg/l. Another model using tobramycin in each exchange predicted that a loading dose of 3 mg/kg followed by 0.3 mg/kg would provide steady-state plasma concentrations of 2.8 to 3.1 mg/l. These data should be useful in treating CAPD patients with tobramycin who have nonperitoneal gram-negative aerobic bacterial infections, as well as those who require the drug for peritonitis.
To establish therapeutic guidelines for vancomycin usage in patients receiving continuous ambulatory peritoneal dialysis (CAPD), we studied single-dose kinetics of vancomycin in CAPD patients. Vancomycin was studied after a 10-mg/kg dose was given intravenously (VAN-IV) or intraperitoneally (VAN-IP). VAN-IV provided a plasma concentration above 10 mg/l at 12 hr, with a t 1/2 of 81 hr. When VAN-IP was given, 65% was absorbed; peak plasma concentrations were only 6.3 mg/l, and t 1/2 was 66 hr. CAPD accounted for only 15% to 17% of total body clearance in both groups. The kinetic principle of superposition was used to predict plasma concentrations after repeated VAN-IP doses. A model with once-a-day dosing predicted that a loading dose of 30 mg/kg followed by 7 mg/kg would achieve steady-state plasma concentrations of 11 to 14.8 mg/l. Another model with vancomycin in each exchange predicted that a loading dose of 30 mg/kg followed by 1.5 mg/kg would provide plasma concentrations in excess of 10 mg/l at 180 hr. These data should be useful in vancomycin treatment of CAPD patients who have nonperitoneal gram-positive bacterial infections, as well as those who have peritonitis.
We studied single-dose cefazolin (CFZ) and cephalexin (CPX) kinetics in continuous ambulatory peritoneal dialysis (CAPD) patients to establish therapeutic guidelines for two cephalosporins commonly used to treat peritonitis in these patients. CFZ, 10 mg/kg, was given intravenously and intraperitoneally, while CPX, 500 mg, was given orally. CFZ led to serum concentrations of 25 microgram/ml at 24 hr, with a half-life (t 1/2) of 33 hr. CAPD accounted for only 20% of total body clearance. When CFZ was given intraperitoneally, 74% of the dose was absorbed and similar serum concentrations had much the same t 1/2. CPX, on the other hand, had a serum t 1/2 of 8.6 hr and resulted in much lower peritoneal concentrations than CFZ. The kinetic principal of superposition provided a model for the prediction of plasma concentrations after repeated intraperitoneal doses of CFZ. The model predicts that a 10-mg/kg intraperitoneal loading dose, followed by 5-mg/kg doses in each exchange the first day and 2.5-mg/kg doses thereafter, will lead to steady-state plasma concentrations of 50 to 65 microgram/ml. The data suggest that CFZ needs be given only intraperitoneally at doses lower than those in current use. CPX probably adds little to the treatment of peritonitis.
To test the hypotheses that the renal parenchymal accumulation kinetics of aminoglycosides can predict nephrotoxicity, we measured renal parenchymal concentrations in rats receiving gentamicin and tobramycin. In addition to comparing the drugs as single daily injections, we also examined the effect of multiple doses versus a single daily dose. Gentamicin accumulated to much greater concentrations in the kidney than did tobramycin. Gentamicin given twice daily accumulated more rapidly and to greater concentrations than did the same total dose given once daily. We conclude that aminoglycoside accumulation in the kidney depends on the drug and dose regimen. These differences may explain relative nephrotoxicities.
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To elucidate abnormalities in the renal microvasculature that could account for the functional disturbances occurring in two well-established models of acute renal failure, we gave rats a single intramuscular injection of glycerol (50%, 10 ml/kg) or daily subcutaneous doses of gentamicin (100 mg/kg/day). Afferent arteriolar diameters were determined by measuring methacrylate vascular casts with SEM. The filtration barrier was examined by both SEM and TEM. The EF area was quantitated. By 3 hr, the glycerol treatment markedly decreased PADs and DADs (PAD 19.1 to 12.0 micrometers, DAD 13.8 to 7.4 micrometers, p less than 0.05). The changes were similar for both inner and outer cortical regions. By 3 days the vasoconstriction was alleviated; however, renal failure persisted. At that time, however, EF area was decreased to 43% of normal. After 10 days of gentamicin treatment, only minimal vasoconstriction occurred in the outer cortex; however, EF area was decreased to a similar degree as observed with the 3-day glycerol-treated animals. There are two phases to glycerol-induced acute renal failure. The first phase (described as readily reversible) is characterized by intense vasoconstriction. The second phase, which is not immediately reversible, is associated with a decreased EF area. Smaller outer cortical afferent arterioles and a decreased fenestral diameter and density of the glomerular endothelium are seen only after gentamicin-induced renal failure is well established (after 10 days of treatment).