Biomedical subjects

M E Brier

Publications and source records attributed to M E Brier.

47 records · Page 3Linked to original sources

PubMed1987

Effect of acute renal failure on insulin disposition in the isolated perfused rat kidney.

The renal disposition of insulin in acute renal failure has not been evaluated. We used the isolated perfused rat kidney to test the hypothesis that acute renal failure (ARF) decreases renal insulin clearance. We used warm ischemia for 45 min, uranyl nitrate 5 mg/kg, ureter ligation, and nonfiltering kidneys as methods of inducing ARF. Comparisons were made with normal control kidneys. The concentrations of insulin in perfusate and urine was determined by radioimmunoassay. Acute renal failure caused significant reductions in glomerular filtration rate, sodium and potassium reabsorption, and an increased urine pH. Warm ischemia and uranyl nitrate toxicity caused a 50% decrease in the renal clearance of insulin. Nonfiltering kidneys cleared insulin at a rate 90% decreased from controls. Ureteral ligation caused a 32% decrease in insulin clearance. Filtration was necessary for insulin to be cleared from perfusate. We conclude that ARF decreased renal insulin clearance through a decrease in insulin uptake from both the tubular lumen and peritubular surface.

Acute Kidney Injury↗

PubMed1987

Kinetics and pharmacodynamics of atrial natriuretic peptide and lithium clearance in the isolated perfused rat kidney.

We used the kinetics of atrial natriuretic peptide (ANP) and fractional lithium excretion to test the hypothesis that ANP-induced natriuresis is related directly to the ANP perfusate concentration and is mediated by a decrease in proximal tubular sodium reabsorption. Wistar rat kidneys were perfused for 90 min after administration of 1 microgram of human ANP. Comparisons were made to control perfusions. ANP had a short half-life (12.4 min) and a renal clearance 6-fold greater than the creatinine clearance. ANP treatment resulted in a significant peak increase in sodium (5.6-fold), lithium (2.1-fold), potassium (2.3-fold) and water (5.1-fold) excretion. The natriuretic response to ANP was delayed 25 min. Exogenous creatinine clearance, perfusion pressure, perfusion flow and renal vascular resistance were not affected. We conclude that the kidney eliminates ANP rapidly by mechanisms that appear to be located primarily in the peritubular circulation. The initial renal response to ANP did not follow perfusate concentrations. Rather, natriuresis increased as ANP concentrations decreased. The relationship was defined by a counterclockwise hysteresis loop. Natriuresis was not mediated by an increased delivery of sodium to the tubule, but may have been due to either a direct or an indirect action of ANP on the kidney.

Absorption↗

PubMed1985

Relationship between rat renal accumulation of gentamicin, tobramycin, and netilmicin and their nephrotoxicities.

Gentamicin, tobramycin, and netilmicin were given to rats in daily doses of either 5 or 20 mg/kg for 30 days to determine the renal accumulation kinetics of the compounds and to correlate steady-state renal parenchymal concentrations with nephrotoxicity. Four rats from each group were sacrificed daily and renal parenchymal tissue concentrations were determined microbiologically. Nephrotoxicity was assessed by changes in creatinine values in serum, renal creatinine clearances, and pathological scores. There was no indication of aminoglycoside-induced nephrotoxicity in any tests performed. The following steady-state levels resulted: 36, 148, and 176 micrograms/g after 5 mg/kg per day and 148, 260, and 510 micrograms/g after 20 mg/kg per day for tobramycin, gentamicin, and netilmicin, respectively. We conclude that aminoglycoside parenchymal accumulation in rats follows this order: tobramycin less than gentamicin less than netilmicin. Therefore, differences in the relative toxicities of gentamicin, tobramycin, and netilmicin do not correlate with the renal parenchymal accumulation of these agents and may be more dependent on intrinsic toxicity to the renal proximal tubule than to the concentration of the aminoglycoside in the kidney.

Animals↗

PubMed1984

Interactions of moxalactam and tobramycin in normal volunteers and in patients with impaired renal function.

In studies of the in vivo and in vitro interactions of moxalactam and tobramycin, normal volunteers and anuric patients were given one of the drugs or both drugs simultaneously, and the antibiotics were incubated separately or in combination in pooled human plasma. In both normal volunteers and patients with renal failure, the rate of elimination of tobramycin increased when the drug was given in combination with moxalactam. In patients with normal renal function, the rate of elimination of moxalactam decreased when the drug was given in combination with tobramycin; in contrast, this value did not decrease when the combination was given to anuric patients. In vitro, neither drug was affected by the presence of the other. Thus, the observed changes in elimination rates apparently are not caused by a chemical interaction that can be demonstrated in vitro. However, they are of sufficient magnitude to be of potential clinical significance.

Anuria↗

PubMed1983

The effect of piperacillin dose on elimination kinetics in renal impairment.

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.

Adult↗

PubMed1983

Mezlocillin kinetics in hepatic insufficiency.

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.

Adult↗

PubMed1983

Tobramycin kinetics during continuous ambulatory peritoneal dialysis.

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.

Adult↗

PubMed1983

Vancomycin kinetics during continuous ambulatory peritoneal dialysis.

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.

Adult↗

PubMed1983

Cefazolin and cephalexin kinetics in continuous ambulatory peritoneal dialysis.

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.

Administration, Oral↗

PubMed1983

Aminoglycoside accumulation kinetics in rat renal parenchyma.

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.

Aminoglycosides↗

PubMed1981

Mezlocillin enteral absorption in rabbits.

To determine the role of enterohepatic recirculation on its nonlinear elimination, we studied the enteral absorption of mezlocillin in rabbits. Mezlocillin was not substantially absorbed from the stomach or duodenum. We conclude that enterohepatic recirculation does not cause the dose-dependent elimination kinetics of mezlocillin.

Animals↗