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Biomedical subjects

A Contrepois

Publications and source records attributed to A Contrepois.

32 records · Page 2Linked to original sources
PubMed1984

Gentamicin, netilmicin, dibekacin, and amikacin nephrotoxicity and its relationship to tubular reabsorption in rabbits.

The role of the tubular reabsorption of aminoglycosides in nephrotoxicity was considered. The tubular reabsorption rate, fractional reabsorption, and net balance, expressed as the excreted to infused aminoglycoside ratio, were concomitantly studied in male rabbits by continuous infusion of gentamicin, netilmicin, dibekacin, and amikacin. Aminoglycoside nephrotoxicity was evaluated by creatinine levels in serum and pathological renal damage after 14 days of a low- or high-dose regimen, comprising either eight, hourly intramuscular injections of gentamicin, netilmicin, or dibekacin (4 mg/kg) or amikacin (16 mg/kg); twelve, hourly intramuscular injections of gentamicin, netilmicin, or dibekacin (15 mg/kg) or amikacin (60 mg/kg); or injections of saline for the control group. Aminoglycosides exhibited three degrees of tubular reabsorption: gentamicin had the highest, netilmicin had the lowest, and dibekacin and amikacin had intermediate degrees of reabsorption. Nephrotoxicity associated with alteration in renal histology was observed with gentamicin and, to a lesser extent, with dibekacin in the high-dose regiment. No nephrotoxicity was noted with netilmicin or amikacin compared with the control group. Concentrations of the aminoglycosides in renal cortex and serum were not predictive of renal toxicity. Except for amikacin, which appeared to exhibit the lowest intrinsic renal toxicity, nephrotoxicity was correlated with the tubular reabsorption of each aminoglycoside. It was concluded that aminoglycoside renal toxicity can be determined by two major factors: importance of transport into tubular cells and intrinsic intracellular toxicity.

Amikacin↗
PubMed1984

Effects of furosemide, piretanide, and water loading on urinary excretion of cefazolin in humans.

Antibiotics and diuretics are often prescribed concomitantly for humans. We compared the effects of two potent loop diuretics, furosemide and piretanide, with those of water loading on the urinary excretion of cefazolin. During a continuous infusion of inulin and cefazolin (10 mg/kg per h), six healthy male volunteers received a single intravenous injection of furosemide (0.3 mg/kg) or piretanide (0.1 mg/kg) or again an oral water load of 15 ml/kg over a 20-min period. In vitro, furosemide at all concentrations tested significantly reduced by about 10% the percentage of cefazolin bound to serum proteins. Piretanide exhibited such an effect only at a concentration of 2 micrograms/ml. Furosemide, piretanide, and water loading significantly and similarly increased the ratio of excreted to infused cefazolin up to 2 h after the injection of diuretic or after oral water intake. In each of the three parts of the experiment, the increase of the urinary flow rate was similar when compared with the control values. Furosemide significantly increased the cefazolin filtered load during the same time. Piretanide significantly enhanced the absolute rate of net cefazolin tubular secretion. Water loading increased the urinary excretion of cefazolin, probably through a reduction in tubular reabsorption. These results suggest that (i) furosemide and piretanide as well as water loading are capable of enhancing renal excretion of cefazolin by different complex mechanisms; (ii) cefazolin undergoes a bidirectional tubular transport; (iii) piretanide might act on the proximal tubule in addition to its main site of action on Henle's loop; and (iv) the effects of both diuretics and of water loading are unlikely to affect in vivo antibiotic activity in humans.

Adult↗
PubMed1984

Renal disposition of ceftazidime illustrated by interferences by probenecid, furosemide, and indomethacin in rabbits.

Excretion of ceftazidime (C), a new cephalosporin antibiotic, has been reported to occur unexpectedly through glomerular filtration only, without being significantly affected by probenecid. We investigated renal tubular disposition of C in rabbits by calculating its rates of fractional excretion, net tubular secretion, and absolute excretion. During continuous intravenous infusion of C, 3 mg of furosemide (F), 15 mg of probenecid (P), or 2 mg of indomethacin (I) per kg was injected intravenously as a bolus. Equilibrium dialysis showed that the percentage of C bound to serum proteins (14 +/- 5%) was not altered by F, P, or I. Fractional excretion of C was 94 +/- 22, 65 +/- 21, 182 +/- 36, and 98 +/- 3% for the drug given alone and after injection of F, P, and I, respectively. For 15 min after P injection, we observed net tubular secretion of C (404 +/- 276 micrograms/min). The C absolute excretion rate was significantly reduced by I compared with the absolute excretion rate for the control (405 +/- 104 versus 696 +/- 157 micrograms/min). We conclude that (i) C undergoes bidirectional transport in the nephron, revealed by the effects of F and P, with a nil net C balance; (ii) F and P have opposite unexpected effects on tubular handling of C, possibly due to competition for C secretion processes; (iii) I reduces C excretion solely by decreasing its glomerular-filtered load; and (iv) tubular handling of C differs from that of previously studied cephalosporins.

Animals↗
PubMed1983

[From serum pharmacokinetics to extravascular pharmacokinetics of antibiotics. Importance of protein binding].

Serum and urinary concentrations of antibiotics are not predictive of their extravascular distribution. Data from an animal model giving access to an extravascular fluid have demonstrated the effects of protein binding on the extravascular diffusion of cephalosporins. A high percentage of protein binding delays extravascular distribution and facilitates accumulation from repeated doses. Moreover, strongly bound drugs may reduce the number of protein-bound cephalosporin molecules by competing for binding sites and interfere with the extravascular distribution of these antibiotics without modifying their serum levels.

Animals↗
PubMed1982

Vancomycin in rabbits: pharmacokinetics, extravascular diffusion, renal excretion and interactions with furosemide.

The pharmacokinetics, renal excretion, protein binding and extravascular diffusion of vancomycin in rabbits were studied. The effects of furosemide on these different parameters also were investigated. We observed a T 1/2 of 55 min and protein binding of 65% as determined in vitro by equilibrium dialysis. Vancomycin appeared to be secreted by renal tubules (fractional excretion: 177 +/- 44%). In vitro, furosemide (5 micrograms/ml) slightly decreased the vancomycin protein binding (from 65 to 57%). Furosemide significantly increased the renal excretion of vancomycin, through a tubular process without any effect on the filtered load. Vancomycin appeared slowly and at low concentrations in the extravascular fluid. The extravascular concentrations were higher when the antibiotic was administered by a 6-hr continuous infusion than when given by a 20-min infusion of the same dose. Our results suggested that the in vivo antibacterial effect to vancomycin could be enhanced by prolonged infusion. Also, it was demonstrated that furosemide has only a small effect on the kinetics of vancomycin.

Animals↗
PubMed1981

Effects of phenylbutazone on extravascular diffusion, protein binding and urinary excretion of cefazolin in rabbits.

The effects of an anti-inflammatory drug, phenylbutazone, on the disposition of a commonly used cephalosporin, cefazolin, were studied in rabbits. The following investigations were made: mathematical analysis of blood levels obtained after i.v bolous injection of cefazolin, alone or combined with phenylbutazone (10 mg/kg), injection 4 hr before; protein binding by ultracentrifugation in vitro; and renal excretion and distribution in extravascular fluid obtained from s.c. tissue cages in vivo. Single i.m. injections of cefazolin (30 mg/kg) were administered either alone or in combination with phenylbutazone (10 or 100 mg/kg i.m.) or 2 or 4 hr before. The mathematical analysis disclosed a competition of phenylbutazone on protein binding of cefazolin. In vitro, phenylbutazone reduced the extent of protein binding of the antibiotic (74-80 to 47-59%). Cefazolin appeared at higher concentrations in extravascular fluid in the presence of phenylbutazone than when administered alone. Phenylbutazone appeared to be responsible for a dose-dependent effect on renal excretion of cefazolin i.e., a reduction of secretion at low doses (10 mg/kg) and a possible reduction of tubular reabsorption at high doses (100 mg/kg). A bidirectional transport of cefazolin in rabbit tubules was thus shown. The interaction of phenylbutazone on the on the disposition of cefazolin appeared also dependent on the time of injection of the former and on the mode of administration of the antibiotic.

Animals↗
PubMed1980

Effects of furosemide on extravascular diffusion, protein binding and urinary excretion of cephalosporins and aminoglycosides in rabbits.

We studied the effects of furosemide on the disposition of cefazolin and gentamicin in rabbits. The following points were investigated: protein binding (PB) by ultracentrifugation in vitro; renal excretion and distribution in extravascular fluid (EF) obtained from s.c. tissue cages in vivo. Single i.m. injections of cefazolin (30 mg/kg) and gentamicin (1.5 mg/kg) alone or in combination with furosemide (0.5, 1 and 5 mg/kg) were made. After furosemide injection, blood and EF levels of gentamicin significantly decreased. Cefazolin blood levels were unchanged. Cefazolin appeared in EF earlier and at higher levels, up to 4 hr after furosemide injection, than when administered alone. Late cefazolin EF levels (8 and 12 hr) were reduced. All these effects were furosemide dose-dependent. Furosemide, in vitro, decreased cefazolin PG from 80 to 50%, whereas PB of gentamicin remained minimal (0--4%). Furosemide significantly increased the renal excretion of cefazolin and gentamicin without any effect on the glomerular filtration rate. A competitive effect of furosemide on the PB of cephradin and netilmicin was also demonstrated in vitro and in vivo. Our studies outline two kinds of interaction between furosemide and antibiotics. With protein-bound drugs, furosemide induced a competitive reduction of PB responsible for earlier EF diffusion and increased glomerular filtered load, but also induced an increased renal excretion by a tubular process. The latter was the only one induced by furosemide on unbound drugs (gentamicin).

Aminoglycosides↗
PubMed1978

Comparative distribution of gentamicin, tobramycin, sisomicin, netilmicin, and amikacin in interstitial fluid in rabbits.

We compared the penetration of five aminoglycosides into interstitial fluid (IF). IF was obtained in rabbits from Silastic tissue cages. Intramuscular injections were made: 1.5 mg/kg per dose for gentamicin (G), tobramycin (T), sisomicin (S), and netilmicin (N) and 7.5 mg/kg per dose for amikacin (A). Serum levels and IF concentrations were studied for 12 h after a single injection. IF levels were also compared in a six-injection study (one injection every 8 h). Peak serum levels were significantly higher with A than with G, T, S, and N, which gave similar concentrations. In IF, G gave the highest levels 1 h after the first injection. At 4 and 8 h, the concentrations achieved with G and A were similar but significantly greater than those achieved with T, S, and N. Twelve hours after a single injection, N gave higher IF levels than the other drugs except A. In the six-injection study, the IF levels of G and A reached 4.6 +/- 1.5 and 5.27 +/- 1.1 microgram/ml, respectively, at 48 h. S and N gave identical concentrations (2.07 +/- 0.25 and 2.42 +/- 0.42 microgram/ml, respectively). T induced the lowest levels (1.17 +/- 0.30 microgram/ml). Thus, in this rabbit model, the IF concentrations achieved with G and A were above the minimal inhibitory concentrations for most susceptible strains. Possible relations between IF aminoglycoside concentrations and therapeutic efficiency or toxicity are pointed out but deserve further studies.

Amikacin↗
PubMed1978

Tissue cage experiments with beta-lactam antibiotics in rabbits.

An animal model in which antibiotic concentrations can be meausred in intersittial fluid (IF) withdrawn from subcutaneous tissue cages has been used. Although the physiological significance of IF is not well established, this model allowed the comparison of 1) two pharmacological forms of the same drug (bacampicillin and ampicillin were compared after a single oral dose; and 2) drugs of the same group in a single i.m. injection study and in a cumulative effect study. These data provide new criteria for clinical choice of antibiotics. A rapid penetration into IF can be explained by a low degree of serum protein binding, but a highly bound drug is not restricted to the intravascular space. In this animal model we have also shown that an 0.25 h i.v. infusion of cephalothin induced higher IF levels than an i.v. bolus injection and an 1 h i.v. infusion. Using a single i.v. bolus injection of various cephalosporins, we have shown that a two open compartment model cannot explain both serum and IF data. Sustained late IF levels suggested the hypothesis of a deep compartment.

Ampicillin↗
PubMed1977

Penetration of cefazolin, cephaloridine, and cefamandole into interstitial fluid in rabbits.

We compared the penetration of three cephalosporins into interstitial fluid. Interstitial fluid was obtained in rabbits from Silastic tissue cages. Cefazolin, cephaloridine, and cefamandole were administered by the intramuscular route (30 mg/kg per injection). Peak blood levels and interstitial concentrations were studied after a single injection. Interstitial levels were also compared in a three-injection study (one injection every 12 h) and in a cumulative effect study (six injections), in which the interval between injections was established for each drug on the basis of its common therapeutic use. After a single injection, cephaloridine activity was detected more rapidly and attained higher levels than the other two drugs within the first 4 h. However, 2 h after the third injection, cefazolin levels in tissue fluid were higher than with cephaloridine. Cefamandole consistently gave the lowest interstitial levels. With all three drugs, detectable concentrations were present in interstitial fluid at a time when no detectable antibiotic was found in serum. In the six-injection study, the interstitial levels obtained with cefazolin were significantly higher than those observed with the other drugs. Our data suggest that cefazolin is a drug of choice due to its high extravascular levels.

Animals↗