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Biomedical subjects

D N Gilbert

Publications and source records attributed to D N Gilbert.

At least 55 records · Page 3Linked to original sources
PubMed1985

Attenuation of experimental tobramycin nephrotoxicity by ticarcillin.

It is well known that in vitro the combination of carbenicillin, ticarcillin, or other antipseudomonal penicillins with gentamicin, tobramycin, or other aminoglycoside antibiotics results in the inactivation of the antibacterial activity of the aminoglycoside. To assess the influence of the in vivo interaction of tobramycin and ticarcillin on experimental nephrotoxicity, male Fischer 344 rats were given either tobramycin alone (120 mg/kg per day), tobramycin (120 mg/kg per day) and ticarcillin (250 mg/kg per day) concomitantly, or the combination of these drugs at the same doses that had been preincubated for 24 h and at the time of delivery contained but 63 and 25%, respectively, of the initial concentrations of tobramycin and ticarcillin as measured by conventional analytical procedures. Initial experiments were conducted to determine the concentrations of the antibiotics in serum achieved after administration of each test solution. After a single dose of the test solution, ticarcillin concentrations in serum were higher and more prolonged in rats given tobramycin plus ticarcillin than in rats given ticarcillin alone. After 7 days of exposure to the test solutions, inulin clearance in animals given tobramycin alone was 0.15 +/- 0.1 (mean +/- 2 standard errors) ml/min per 100 g of body weight as compared with 0.53 +/- 0.1 in rats given tobramycin and ticarcillin concomitantly, 0.59 +/- 0.1 in animals given the partially inactivated tobramycin-ticarcillin mixture, and 0.79 +/- 0.1 in control rats. Although there was some improvement in inulin clearance in the group containing tobramycin alone, the three treatment groups maintained the same rank relationship in inulin clearance through 14 days of treatment. Real histology confirmed the attenuation of tubular injury in animals given tobramycin and ticarcillin concomitantly. There was no evidence of toxicity from the presumed inactivation complexes of tobramycin-ticarcillin. These results document an in vivo protective effect of ticarcillin on experimental tobramycin nephrotoxicity.

Animals↗
PubMed1985

An evaluation of antipseudomonal antimicrobic agents.

The data summarized above indicate that major strides have been made in the use of beta-lactam antibiotics for serious infections due to P. aeruginosa. Emergence of resistance during therapy is a worrisome feature of the antipseudomonal beta-lactams. It is also disturbing that in no animal model of infection has beta-lactam monotherapy been superior to aminoglycoside monotherapy or the combination of an aminoglycoside with an antipseudomonal penicillin. Imipenem, used alone, has equalled aminoglycoside antibacterial activity in some experimental settings and may be an exception. In most hospitals, aminoglycoside resistance occurs at a low and predictable incidence. Aminoglycoside nephrotoxicity is infrequent, mild in severity, and reversible. The quinolone family appears promising but clinical studies are pending. Based on the available data, it appears that the standard therapy of serious life-threatening infection due to P. aeruginosa remains the combination of an aminoglycoside and an antipseudomonal penicillin.

Aminoglycosides↗
PubMed1985

Experimental gentamicin nephrotoxicity: effect of streptozotocin-induced diabetes.

To determine the effect of diabetes mellitus on gentamicin nephrotoxicity we treated male F344 rats with streptozotocin 22 mg/kg (DM rats). DM rats were compared to controls (C) and nondiabetic rats ingesting the osmotic diuretic isosorbide administered to simulate glycosuric diuresis (C/I). Base-line C/I renal function and histology did not differ from C. However, in DM rats base-line inulin clearance (CIN) was 20% lower, and renal cortical slice uptake of p-aminohippurate was reduced compared to C and C/I. DM rats also had foci of renal tubular epithelial dysplasia not seen in C or C/I. Gentamicin was administered at 40 mg/kg-day to C and C/I and 32 mg/kg-day to DM rats to adjust for base-line CIN. Acute tubular necrosis, associated with depression of CIN and renal cortical p-aminohippurate and N-methylnicotinamide uptake, developed in all three groups. There were no differences between C and C/I. However, the degree of acute tubular necrosis and dysfunction was less in DM rats than C and C/I. Renal cortical gentamicin accumulation was also slower in DM than either C or C/I, and changes in renal cortical gentamicin over time followed a different pattern in DM rats. These results indicate that 1) attenuation of gentamicin injury in DM rats may be related to reduced accumulation of gentamicin by the renal cortex, 2) this reduced accumulation may be due to subtle baseline tubular injury mediated by streptozotocin or the diabetic state, and 3) osmotic diuresis does not account for attenuation of renal injury in DM.

Animals↗
PubMed1984

Nephrotoxicity of the constituents of the gentamicin complex.

Commercial gentamicin C is a mixture of gentamicin C1, C1a, and C2. The nephrotoxicity of each of these constituents was compared with that of the gentamicin complex. After seven days the mean creatinine level in serum was 0.8 mg/dl in rats given C2 and 0.5 mg/dl in rats given C1, C1a, or the gentamicin complex (P less than .001). Toxicity attributable to C1a was not detected until day 14, and only minimal toxicity was noted in C1-treated rats after 21 days. Nephrotoxicity caused by the gentamicin complex was similar to that caused by C2. By a new high-pressure liquid chromatographic method, the renal concentration of C1, C1a, and C2 was quantified in rats given the gentamicin complex. The results indicated an early, preferential renal accumulation of C2. Subsequently, the C2 content of 12 commercial lots of gentamicin C was measured. The C2 concentration ranged from 12.4 to 20.1 mg/ml. In short, experimental nephrotoxicity from gentamicin C is largely the result of the C2 constituent, and the concentration of this constituent in commercial preparations of gentamicin varies by as much as 7.7 mg/dl.

Animals↗
PubMed1984

Increasing dietary calcium moderates experimental gentamicin nephrotoxicity.

Because calcium has been reported to modify gentamicin binding to its proximal tubular brush border membrane receptor, we studied the effects of dietary calcium loading and subsequent hypercalciuria on experimental gentamicin nephrotoxicity. Male Fischer 344 rats were fed one of two diets that were identical except for calcium carbonate content: normal (0.5%) and high (4%). The high-calcium diet made rats hypercalciuric but there were no differences between the two groups in inulin clearance, sodium or osmolar excretion, or serum calcium prior to gentamicin administration. Animals on both diets were treated with gentamicin, 20 mg/kg b.i.d., for periods of 3 to 21 days. Both groups developed acute renal failure, but animals on the high-calcium diet had less severe acute toxic injury, as evidenced by studies of inulin clearance, renal histology, and in vitro cortical uptake of NMN and PAH. Furthermore, calcium-loaded animals tended to have lower peak renal cortical gentamicin levels during the period of acute toxicity. The mechanism by which increased dietary calcium protects against gentamicin nephrotoxicity remains speculative. Calcium and gentamicin may compete for the same brush border receptor or alternatively parathyroid suppression may result in diminution in tubular cell membrane drug binding sites. The possibility that high-calcium diets exert a nonspecific salutory effect on proximal tubular cell integrity has not been excluded.

Animals↗
PubMed1984

The influence of aminoglycoside antibiotics on the in vitro function of rat liver ribosomes.

There are few studies of the influence of aminoglycoside antibiotics on the ribosomes of higher eukaryotic organisms. To this end, cytoplasmic ribosomes were prepared from rat liver. In vitro, poly(U)-directed ribosome protein synthesis was studied in the presence and absence of selected aminoglycosides. Misreading of poly(U) was also assessed. Consistent with earlier studies using different sources of ribosomes, paromomycin inhibited cell-free protein synthesis and caused poly(U) misreading. In contrast to the findings of other studies in cell-free ribosomes of eukaryotic organisms, netilmicin, tobramycin, and neomycin were most active in inhibiting protein synthesis, and gentamicin C2 and neomycin caused appreciable misreading. Thus the previous suggestion that a paromamine fragment (found in paromomycin) might be a structural requirement for in vitro inhibition of protein synthesis and misreading is not substantiated by the results in rat liver ribosomes. Commercial gentamicin C is a mixture of gentamicins C1, C1a, and C2. Despite nearly identical chemical structures, the three constituents displayed greatly different propensities for inducing poly(U) misreading. C2 was the most active, followed by C1a. In summary, selected aminoglycoside antibiotics caused inhibition and mistranslation of poly(U) messenger in an in vitro ribosome system prepared from rat liver. These effects were not limited to paromamine-containing aminoglycoside antibiotics. Gentamicin C2 caused much more poly(U) misreading than the other two constituents of the gentamicin C complex.

Aminoglycosides↗
PubMed1982

Sex-related differences in the susceptibility of rats to gentamicin nephrotoxicity.

Age-matched male and female Fischer 344 rats were treated with gentamicin, 40 mg/kg of animal body weight per day, for three to 21 days. Renal dysfunction was less severe in females as measured by concentrations of blood urea nitrogen and creatinine and by cortical slice uptake of p-aminohippuric acid and N1-methylnicotinamide chloride. Also, cortical concentrations of gentamicin in females were lower than in males. Neither exogenous testosterone administered to adult females nor castration of prepubertal males changed the pattern of dysfunction. These results show that sex affects susceptibility to aminoglycoside nephrotoxicity by mechanisms that are undefined but that are apparently unrelated to testosterone. The variable of sex needs to be considered in interpreting the results of studies of experimental aminoglycoside nephrotoxicity.

Animals↗
PubMed1982

Gentamicin does not chelate calcium.

The influence of increasing gentamicin concentrations on ionized calcium concentration was determined in pH-controlled, phosphate-buffered saline and normal human serum with an ion-specific calcium electrode. No evidence of calcium chelation was found.

Calcium↗
PubMed1982

Reduction of experimental gentamicin nephrotoxicity in rats by dietary calcium loading.

Since gentamicin accumulates in the renal cortex before renal failure and calcium reduces gentamicin binding to cell membranes, we examined the effect of dietary calcium loading on gentamicin toxicity in male F344 rats. Rats were fed either a normal (0.5%)- or a high (4%)-calcium-content chow. Calcium loading did not alter inulin clearance, urinary excretion of sodium or total osmoles, or serum ionized calcium. However, calcium loading caused elevation of urinary calcium excretion and lowered urinary cyclic AMP levels. The data suggest that calcium loading may have slowed the accumulation of gentamicin (40 mg/kg per day) by the renal cortex. Histological and functional evidence of nephrotoxicity was delayed in onset and attenuated in magnitude. The results indicate that dietary calcium loading reduces experimental gentamicin nephrotoxicity. Protection may be associated with slower renal cortical accumulation of gentamicin. Calcium-dependent membrane or intracellular events may mediate this effect.

Animals↗
PubMed1982

Gentamicin nephrotoxicity. I. Degree and permanence of acquired insensitivity.

Insensitivity to the nephrotoxic effects of gentamicin develops in F344 rats during the course of gentamicin-mediated acute renal failure. Functional and structural recovery occur thereafter in spite of continued gentamicin administration. To determine the degree of insensitivity, we compared structural and functional recovery of rats treated continuously with gentamicin to rats in which gentamicin was stopped after 14 days, at the height of dysfunction. Continued treatment did not reduce the rate or ultimate degree of recovery of structure, CIn, or in vitro renal cortical PAH uptake; however, both the rate and degree of recovery of NMN uptake were reduced in continuously treated animals. Furthermore, doubling the dose of gentamicin during the recovery period overcame insensitivity, causing a second episode of acute renal failure. The permanence of insensitivity was examined by re-treating rats 6 months after recovery from gentamicin-mediated acute renal failure. There was no evidence of residual resistance to gentamicin nephrotoxicity in these animals. These results indicate that although gentamicin insensitivity is substantial, it is not complete, as indicated by low-grade, ongoing tubular toxicity to the organic base transport system and sensitivity to higher doses of gentamicin. Furthermore, insensitivity is a transient phenomenon.

Acute Kidney Injury↗
PubMed1982

Gentamicin nephrotoxicity. II. Definition of conditions necessary to induce acquired insensitivity.

Acquired insensitivity to the nephrotoxic effects of gentamicin develops in Fischer 344 rats after 10 to 14 days' treatment after development of histologic acute tubular necrosis in a setting of extensive histologic regeneration. To determine the relative importance of aminoglycoside exposure, necrosis, and regeneration in the induction of insensitivity, we examined the effect on gentamicin toxicity of prior non-aminoglycoside-mediated tubular necrosis, antecedent nonnecrotizing aminoglycoside exposure, and unilateral Nx-induced renal tubular hyperplasia. Pretreatment with potassium dichromate, which causes tubular necrosis in the same part of the renal cortex as gentamicin, reduced gentamicin-mediated elevation of Scr but had little effect on gentamicin-related tubular dysfunction or structural damage. Pretreatment with netilmicin, which does not cause tubular necrosis, increased the sensitivity of the kidney to gentamicin; toxicity occurred earlier and was more severe. Antecedent unilateral Nx had no demonstrable effect on susceptibility to gentamicin-associated dysfunction, but histologic renal tubular epithelial regeneration and recovery from dysfunction occurred earlier, These results suggest that necrosis and/or regeneration is the major prerequisite for development of gentamicin insensitivity and that the onset of insensitivity is temporally related to the appearance of necrosis and regeneration. However, non-aminoglycoside-mediated necrosis and regeneration fail to fully-re-create insensitivity, suggesting that exposure to gentamicin is also necessary.

Acute Kidney Injury↗
PubMed1981

Suppression of granulopoiesis by T-lymphocytes in two patients with disseminated mycobacterial infection.

Two patients with disseminated mycobacterial infection presented with severe neutropenia and hematopoietic failure. Marrow cells were obtained from each patient and were cultured in methylcellulose before and after the removal of mononuclear phagocytes, T-lymphocytes, or both from the marrow cell suspension. Glucocorticosteroid-resistant T-lymphocytes markedly inhibited granulopoiesis, but mononuclear phagocytes did not. Indomethacin inhibition of prostaglandin synthesis did not influence suppression of colony growth by the inhibitory lymphocytes. In the one patient who responded favorably to antituberculous therapy, the in-vitro T-lymphocyte inhibition of granulopoiesis disappeared as the neutropenia resolved. Thus, in some patients with disseminated mycobacterial infection, clinical bone marrow failure may be mediated, at least partly, by T-lymphocytes that suppress hematopoiesis.

Adult↗
PubMed1981

Surgical approach to extensive suppurative thrombophlebitis of the central veins of the chest.

Suppurative thrombophlebitis is a potentially lethal intravascular infection associated with the usage of intravenous catheters. Conventional approaches to management include ligation and excision of involved venous structures. These measures may not be feasible in all situations. This paper describes the successful medical/surgical management of a patient with suppurative thrombophlebitis of the major vessels of the chest. When suppurative thrombophlebitis extends into the large central veins and antibiotic therapy fails, surgical intervention may be necessary.

Adolescent↗
PubMed1981

Comparative nephrotoxicity of dibekacin and gentamicin in rats.

To evaluate the nephrotoxicity of the new aminoglycoside, dibekacin, relative to gentamicin, we administered both drugs in doses of 40 and 120 mg/kg per day to male and female Fischer 344 rats. At sacrifice, we determined serum creatinine, in vitro renal cortical uptake of 14C N-methyl nicotinamide and para-aminohippurate, renal cortical antibiotic concentrations, and real histology. Dibekacin and gentamicin were similar in overall toxicity. Dibekacin differed from gentamicin and other aminoglycosides (1) in failing to cause early transient stimulation of para-aminohippurate uptake in male rats and (2) in the location of histologic damage at the 120 mg/kg dose. We conclude that: 1) in this model, dibekacin is comparable to gentamicin in nephrotoxic potential, and 2) the lack of early stimulation of para-aminohippurate uptake in male rates after dibekacin treatment may be related to greater initial injury to the late proximal tubule than is caused by gentamicin.

Animals↗