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Biomedical subjects

W M Bennett

Publications and source records attributed to W M Bennett.

At least 181 records · Page 10Linked to original sources
PubMed1988

Early use of OKT3 monoclonal antibody in renal transplantation to prevent rejection.

OKT3 monoclonal anti-T cell antibody was used during the first 2 weeks following cadaveric renal transplantation to prevent rejection. When compared with a control group receiving triple immunosuppression with cyclosporine, azathioprine, and prednisone, the OKT3, azathioprine, and prednisone group had significantly fewer acute rejections during the first month (6% v 50%; P less than 0.01), and the mean time of onset of the first rejection was significantly delayed (day 47 v day 8; P less than 0.01) in the OKT3 prophylaxis group. OKT3 was administered intraoperatively safely and without complications on the day of transplantation. The well-reported first dose reaction to OKT3 was similar in these patients when compared with patients receiving OKT3 for treatment of rejection. Anti-OKT3 antibody development occurred in half of the patients receiving OKT3, and did not prevent the subsequent use of OKT3 in these patients, whose rejections following OKT3 prophylaxis were steroid reversible. There were no deaths among the patients receiving prophylactic OKT3, and during a 15-month follow-up, only three of 34 kidneys were lost for any reason. In addition to its use for primary and steroid-resistant rejection, OKT3 may be useful early after transplantation to prevent rejection.

Antibodies, Anti-Idiotypic↗
PubMed1988

Vancomycin pharmacokinetics, renal handling, and nonrenal clearances in normal human subjects.

The renal handling of vancomycin is unknown. Previously reported studies have not achieved steady-state conditions with constant vancomycin concentrations. We measured systemic vancomycin clearance simultaneously with the renal clearances of vancomycin, creatinine, inulin, and para-aminohippurate in nine healthy subjects at steady-state serum vancomycin concentrations of 7 and 14 mg/L. For all steady-state observations the renal clearance of vancomycin was 89 +/- 11 ml/min (mean +/- SE), the clearance of inulin 105 +/- 9 ml/min, the clearance of creatinine 117 +/- 9 ml/min, and the clearance of para-aminohippuric acid 496 +/- 41 ml/min. The systemic clearance of vancomycin was 131 +/- 7 ml/min. The clearances of creatinine, inulin, and para-aminohippuric acid and the renal clearance of vancomycin were not statistically different at both steady-state vancomycin concentrations. The ratio of the renal clearance of vancomycin to the clearance of inulin was 0.89 +/- 0.06 and to creatinine clearance 0.79 +/- 0.05. Both ratios were independent of vancomycin concentration, urine flow rate, and filtration fraction. The systemic clearance of vancomycin was 10% greater at serum vancomycin concentrations of 14 mg/L than at 7 mg/L (p less than 0.05) because of an increase in the nonrenal clearance. Therefore in healthy subjects, 30% of the systemic vancomycin clearance is by nonrenal mechanisms and this nonrenal clearance is concentration dependent. Assuming protein binding to be between 10% and 20%, renal vancomycin excretion is predominantly by glomerular filtration. Small amounts of tubular vancomycin transport cannot be excluded by these techniques.

Adult↗
PubMed1988

Effects of a fish oil dietary supplement on endotoxin-induced ocular inflammation.

We compared the effects of fish oil versus corn oil dietary supplements on two rabbit models of uveitis induced by either intravenous (IV) or intravitreal (IVT) Escherichia coli endotoxin. Addition of fish oil to a standard diet consistently diminished the rise in aqueous humor prostaglandin E2 levels 24 hours after IVT endotoxin injection or 3 hours following IV endotoxin injection. Aqueous humor thromboxane B2 levels following IV or IVT endotoxin injection were also lower in rabbits fed a fish oil supplemented diet. However, the fish oil diet resulted in only a modest attenuation of increases in ocular vascular permeability following either IVT or IV endotoxin injection. Fish oil supplementation inconsistently reduced leukocyte infiltration into the anterior chamber following IVT endotoxin. In contrast to the reported ability of fish oil dietary supplements to reduce corneal inflammation, these models of anterior uveal inflammation do not seem to be altered in a clinically significant manner.

Animals↗
PubMed1988

The influence of tobramycin dosage regimens on nephrotoxicity, ototoxicity, and antibacterial efficacy in a rat model of subcutaneous abscess.

The influence of dosage regimen on the nephrotoxicity, ototoxicity, and antibacterial efficacy of tobramycin was assessed in Fisher rats with Pseudomonas aeruginosa subcutaneous abscesses. A subcutaneous tobramycin dose of 10 mg/kg every 4 h resulted in peak and trough serum concentrations that approximated those currently recommended for patients. Subsequently, the influence of this subcutaneous dosage regimen was compared with three other regimens that administered the same total daily dose: 20 mg every 8 h, 30 mg every 12 h, and 60 mg every 24 h. Renal injury was assessed by measuring inulin clearance and in vivo synthesis of renal DNA and by histopathology. Cochlear histology was also assessed. The number of P. aeruginosa per abscess was quantitated. In animals with infected abscesses, there was a consistent trend of greater kidney injury with the more-frequent dosage regimens. There was no evidence of cochlear toxicity in any group. All regimens were equally effective in reducing the number of P. aeruginosa in subcutaneous abscesses.

Abscess↗
PubMed1988

Cyclosporin A and pressor responsiveness in sheep.

Pressor response to graded infusion of angiotensin II, noradrenaline, arginine-vasopressin, and serotonin and blood pressure change following indomethacin, an inhibitor of cyclooxygenase, were examined in conscious sheep, before and during the development of cyclosporin A-induced hypertension. Cyclosporin caused an increase in mean blood pressure from 68 +/- 2 to 82 +/- 3 mm Hg (p less than 0.001) and in heart rate from 67 +/- 4 to 91 +/- 4 beats/min (p less than 0.001). Pressor and heart rate responses to all substances tested were not changed by cyclosporin treatment suggesting that changes in pressor responsiveness are unlikely to be involved in the development of cyclosporin hypertension in sheep.

Angiotensin II↗
PubMed1988

Dialysis in the management of pregnant patients with renal insufficiency.

Successful pregnancy in patients on dialysis is uncommon because of a high rate of infertility and complications. The use of hemodialysis to manage pregnant patients needing dialysis has been well reported. However, to our knowledge, only 2 previous cases of pregnant patients using chronic ambulatory peritoneal dialysis (CAPD) have been reported. We discuss 14 pregnancies in 13 women in whom dialysis was used in the management of their pregnancies. Ten pregnancies were successful. Included are 5 successful pregnancies out of 8 managed with CAPD or chronic cycling peritoneal dialysis (CCPD). In comparing the cases managed with CAPD to those managed with hemodialysis, CAPD seems to offer several advantages. These include a more constant biochemical and extracellular environment for the fetus, higher hematocrit levels, infrequent episodes of hypotension, and no heparin requirement. In addition, intraperitoneal insulin facilitates the management of blood glucose in diabetics, and intraperitoneal magnesium facilitates the management of premature labor. Infection, loss of intraperitoneal volume, and loss of peritoneal clearances for solutes and water were not found to be problems.

Adult↗
PubMed1988

Selective enhancement of thromboxane in macrophages and kidneys in cyclosporine-induced nephrotoxicity. Dietary protection by fish oil.

Cyclosporine (CsA) associated renal dysfunction is related in part to renal vasoconstriction. To identify the role of cyclooxygenase metabolites in the induction of vasoconstriction, we analyzed the effect of CsA on the synthesis of thromboxane (TxA2) prostacyclin (PGI2) and prostaglandin E2 (PGE2) in the kidney and peritoneal macrophages. Groups of rats were pair-fed diets enriched with 20% fish oil (FO) or corn oil (CO) for 4 weeks and then were injected with CsA 12.5 mg/kg/day i.p. for 2 weeks. CsA induced the synthesis of TxA2 and modestly reduced PGE2 and PGI2 in renal cortex and peritoneal macrophages. Feeding rats a diet enriched in FO containing omega-3 fatty acids as compared with CO without these fatty acids suppressed the increase in TxA2 and decreased the vasodilators PGE2 and PGI2 in the kidney and peritoneal macrophages, while modifying the decrease in the glomerular filtration rate and vacuolization in proximal convoluted tubules characteristic of rodent CsA-associated nephrotoxicity. Thus, CsA-initiated renal vasoconstriction is related to an increase in the vasoconstrictive Tx molecule and the reduction in vasodilator metabolites. Intrarenal macrophages represent a likely source of this Tx production. Feeding rats diets containing omega-3 fatty acids, known to be competitive inhibitors of cyclooxygenase metabolites, prevents CsA from selectively increasing TxA2 and preserves renal function.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Significance of delayed graft function in cyclosporine-treated recipients of cadaver kidney transplants.

Many transplant teams are reluctant to initiate cyclosporine immunosuppression in recipients of cadaver kidney grafts with delayed graft function (DGF). The renal function of cadaver kidney grafts in cyclosporine-treated recipients was compared in 47 recipients with DGF and 57 without DGF. Regardless of initial renal function, all recipients received prednisone, azathioprine, and oral cyclosporine 5 mg/kg/day or its intravenous equivalent. All kidneys were flushed with ice-cold intracellular electrolyte solution and cold-stored for 15-54 hr (mean of 31 hr) prior to transplantation at our hospital between April 10, 1985 and November 30, 1986. Rejection crises were treated with high-dose steroids or OKT3. Cyclosporine was discontinued during courses of OKT3. Recipients with DGF had significantly higher one-month serum creatinine nadirs (2.6 +/- 1.8 mg/dl vs. 1.5 +/- 0.5 mg/dl). Actuarial graft survivals were not significantly different at one year (82.2 +/- 5.5% vs. 82.6 +/- 6.4%, all graft losses included). Mean serum creatinine levels at six months and twelve months after grafting were not significantly different (1.7 +/- 0.4 mg/dl vs. 1.8 +/- 1.2 mg/dl and 2.0 +/- 0.5 vs. 1.7 +/- 0.7 mg/dl, respectively). Delayed graft function following cadaver kidney transplantation does not adversely affect intermediate term function of kidney grafts flushed with intracellular electrolyte solution and cold-stored until transplantation when a low-dose cyclosporine induction protocol is used and cyclosporine is discontinued during OKT3 administration.

Cadaver↗
PubMed1988

Effectiveness of a second course of OKT3 monoclonal anti-T cell antibody for treatment of renal allograft rejection.

A second course of OKT3 monoclonal anti-T cell antibody was given to 21 recipients of kidney transplants. Rejections reversed in 43% of patients in whom 95% of rejections had reversed with their initial OKT3 course. Reversal was highly dependent upon the timing of rejection, anti-OKT3 antibody production, and T cell CD3 modulation. Rejections treated greater than 90 days after transplantation were resistant to OKT3 reversal. High-titer anti-OKT3 antibodies prevented OKT3 reversal of rejection, and effective CD3 (the cell surface target of OKT3) modulation was necessary for successful OKT3 reversal of rejection. Reexposure to OKT3 further stimulated anti-OKT3 antibody production and broadened the specificity of the antibodies produced. OKT3 can effectively and safely be used a second time for treatment of early T cell-mediated renal allograft rejections if high-titer anti-OKT3 antibodies have not been made.

Adolescent↗
PubMed1988

Ciprofloxacin activity in cyst fluid from polycystic kidneys.

Renal cyst infection in patients with polycystic kidney disease (PKD) is often unresponsive to standard antimicrobial therapy, in part because of the failure of most antibiotics to adequately penetrate cyst fluid. Ciprofloxacin, a new quinolone antibiotic, possesses in vitro activity against most pathogens likely to be encountered in renal cyst infection. To study the potential usefulness of ciprofloxacin for the treatment of cyst infection, fluid from 70 cysts was obtained from seven patients with polycystic kidney disease who were receiving the drug. Cysts were categorized as nongradient or gradient by the sodium concentration in the fluid. The ciprofloxacin concentration within cysts was measured, and the cyst fluid bactericidal activity against likely cyst fluid pathogens was determined. The mean (+/- standard error) ciprofloxacin concentration was 12.7 +/- 2.9 micrograms/ml. Preferential accumulation of ciprofloxacin occurred in gradient cysts; these levels exceeded levels in serum by more than fourfold. Cyst fluid bactericidal activity titers were uniformly high against Escherichia coli and Proteus mirabilis, while less activity was observed against Streptococcus faecalis, Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis.

Adult↗
PubMed1988

Microsomal protein synthesis inhibition: an early manifestation of gentamicin nephrotoxicity.

Aminoglycoside antibiotics achieve bacterial killing by binding to bacterial ribosomes and inhibiting protein synthesis. To examine whether similar mechanisms could be present in renal tubular cells prior to the onset of overt proximal tubular necrosis due to these drugs, we isolated microsomes from Fischer rats given 20 mg/kg gentamicin every 12 h subcutaneously for 2 days and from vehicle-injected controls. Concomitant studies of renal structure, function, and mitochondrial respiration were carried out. [3H]leucine incorporation into renal microsomes of treated animals was reduced by 21.9% (P less than 0.01), whereas brain and liver microsomes from the same animals were unaffected. Gentamicin concentration in the renal microsomal preparation was 56 micrograms/ml, a value 7- to 10-fold above concentrations necessary to inhibit bacterial growth. Conventional renal function studies were normal (blood urea, serum creatinine, creatinine clearance). Treated animals showed only a mild reduction of inulin clearance, 0.71 compared with 0.93 ml.min-1.100 g-1 in controls (P less than 0.05), and an increase in urinary excretion of N-acetylglucosaminidase of 20 compared with 14.8 units/l (P less than 0.05). Renal slice transport of p-aminohippuric acid, tetraethylammonium, and the fractional excretion of sodium were well preserved. There was no evidence, as seen by light microscopy, of proximal tubular necrosis. Mitochondrial cytochrome concentrations were normal and respiratory activities only slightly reduced. Processes similar to those responsible for bacterial killing could be involved in experimental gentamicin nephrotoxicity before overt cellular necrosis.

Animals↗
PubMed1988

Anatomical heterogeneity of parathyroid glands in posttransplant hyperparathyroidism.

Successful renal transplantation may be complicated by persistent hyperparathyroidism due to diffuse parathyroid hyperplasia remaining from a prolonged period of pretransplant chronic renal failure treatment. Posttransplant hyperparathyroidism is distinct from primary hyperparathyroidism, being characterized by multiple gland involvement and diffuse hyperplasia rather than a single adenoma. The gross pathologic anatomy of the parathyroid glands was assessed in 17 successful renal transplant recipients. Individual and total gland volumes were measured at the time of total parathyroidectomy and forearm reimplantation. Parathyroid hyperplasia was heterogenous in both location and gland size. Right-sided glands were enlarged more than left-sided ones. Subjects with primary tubulointerstitial disease exhibited greater hyperplasia than patients with glomerular disorders. Clinicians should be aware of the heterogeneity of the gland enlargement in patients with diffuse parathyroid hyperplasia, so that these patients are not misdiagnosed as suffering from adenomatous parathyroid disease.

Adult↗
PubMed1988

Effect of animal sex on experimental ciclosporin nephrotoxicity.

UNLABELLED: Experimental ciclosporin (CSA) nephrotoxicity is reported to be more severe in male versus female rodents. To investigate these sex differences further, groups of male and female Sprague-Dawley rats were pair fed and given either CSA 50 mg/kg or olive oil vehicle by gavage daily for 5 days. Both groups of treated animals showed azotemia and depression of CIn but there were no sex differences. CSA levels were 5,820 ng/ml in females and 6,480 ng/ml in males (p = NS). Although CSA did not produce enzymuria in either sex, females showed more extensive proximal tubular cell vacuolization. CONCLUSION: Female Sprague-Dawley rats are equally as susceptible to CSA nephrotoxicity as males. Strain differences or experimental design may account for apparently conflicting results in the literature.

Animals↗
PubMed1988

Transmission electron microscopy of urinary sediment in the assessment of aminoglycoside nephrotoxicity in the rat.

Transmission electron microscopy was used to study urine sediment and renal tissue from Fischer rats treated with gentamicin or tobramycin 40 mg/kg/day or sterile water (control) subcutaneously for 5 or 10 days. Renal function was assessed by serum urea nitrogen and 24-hour creatinine clearance. Urine sediment was examined for myeloid bodies and renal tubule cells. After 5 days, the renal function was not different, but myeloid bodies, renal tubule cells, and abnormal renal morphology were found only in tobramycin-treated animals. After 10 days, serum urea nitrogen was higher (p less than 0.05) and creatinine clearance lower (p less than 0.01) in treated than control animals. Myeloid bodies and renal tubule cells were found uniformly in treated animals. Transmission electron microscopy kidneys revealed abnormalities in treated animals, but focal tubular necrosis was found only in gentamicin-treated animals. This study using urinary sediment transmission electron microscopy as a sensitive technique reveals that tobramycin produces earlier but less severe aminoglycoside nephrotoxicity than gentamicin. Renal pathological changes may occur despite the absence of major decreases in renal function.

Aminoglycosides↗
PubMed1988

Chronic tubulointerstitial nephritis and renal insufficiency associated with long-term "subtherapeutic" gentamicin.

To determine whether long-term "subtherapeutic" concentrations of aminoglycoside produce chronic tubulointerstitial nephropathy, Fisher rats were given gentamicin, 20 mg/kg/day, for up to 6 months via indwelling osmotic infusion pumps. Studies included renal histology, autoradiographic quantitation of renal cell tritiated thymidine uptake, renal function and renal cortical gentamicin assay. Acute proximal tubular injury, without tubular necrosis, followed by recovery, occurred during the first month. Subsequently only mild, nonprogressive tubulointerstitial changes and a twofold increase in tubular cell turnover were observed. Inulin clearance fell more than 50% during the 6 months of treatment compared with 10% in age-matched controls. Serum creatinine and creatinine clearance overestimated glomerular filtration rate during treatment and did not distinguish treated animals from controls. During the month after 6 months of gentamicin, tubular microcystic changes and active tubulointerstitial nephritis developed, with a continued fall in inulin clearance. In summary, gentamicin, in "subtherapeutic" doses, produces mild chronic tubulointerstitial nephritis with progressive renal failure. Cessation of treatment is associated with microcystic and inflammatory changes, suggesting that the renal response to tubular injury can be dissociated from the amount of toxin in the renal cortex. Keeping serum aminoglycoside levels below accepted therapeutic range for 6 months did not preclude nephrotoxicity.

Animals↗