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Biomedical subjects

W M Bennett

Publications and source records attributed to W M Bennett.

At least 145 records · Page 8Linked to original sources
PubMed1991

Long-term protection of polyaspartic acid in experimental gentamicin nephrotoxicity.

Polyaspartic Acid (PAA) protects the kidney from experimental gentamicin nephrotoxicity despite large increases in renal cortical gentamicin content. In these experiments, prominent cytoplasmic vacuoles were noted in all animals that received PAA with or without gentamicin. The present study showed that there were no renal structural or functional consequences of PAA given alone or with gentamicin for up to 14 days, followed by a 16-week washout period. Creatinine clearance was similar to that of controls in animals that received gentamicin and in those that received PAA alone. Thus, complete functional protection was conferred by PAA and gentamicin, confirming previous reports from our laboratory. There was no protection by PAA from the nephrotoxic effects of mercuric chloride and cis-platinum.

Animals↗
PubMed1991

Cyclosporine-induced renal dysfunction: correlations between cellular events and whole kidney function.

The main adverse reaction to the immunosuppressive drug cyclosporine is dose-dependent renal dysfunction. Although renal vasoconstriction without major tubular dysfunction is usually noted, recent studies have demonstrated an inhibition of renal cortical microsomal protein synthesis. Sprague-Dawley rats and appropriate pair-fed controls were given cyclosporine orally in doses of 5, 10, 25, and 50 mg/kg/day for periods up to 10 days. A dose-dependent decline in glomerular filtration rate and effective renal plasma flow was maximal by day 3 and did not worsen despite continued dosing. Microsomal protein synthesis as measured by [3H]leucine incorporation was also depressed in a dose-dependent fashion; however, inhibition did not reach the nadir until day 4, 1 day after renal dysfunction was established. When cyclosporine was discontinued, microsomal protein synthesis was normalized by 4 days after drug withdrawal; in contrast, the return of glomerular filtration rate and effective renal plasma flow to normal required 8 days after drug discontinuation. Tubular function as measured by fractional excretion of lithium, enzymuria, and urinary osmolality was well maintained despite the depression of renal hemodynamics. There was no evidence of tubular necrosis by light or electron microscopy. Although cyclosporine produces reductions in renal microsomal protein synthesis, measured by "run-off" translation assays, these effects appear unlikely to be the direct cause of acute renal dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

A multicenter clinical trial of epoetin beta for anemia of end-stage renal disease.

Patients with anemia of end-stage renal disease were studied for 36 weeks to determine efficacy, safety, and long-term benefits of epoetin beta administration. A total of 131 patients participated in the 12-week, double-blind, placebo-controlled portion of the multicenter study. For the first 6 weeks (fixed-dose period), patients were randomized to receive 100 U/kg of epoetin beta or placebo thrice weekly; in the second 6 weeks (dose-adjustment period), the dose of epoetin beta ranged from 50 to 150 U/kg thrice weekly. Of the 131 patients who entered the placebo-controlled period, 122 crossed over to a 24-week open-label period, where all patients received active drug and doses of epoetin beta could be individually titrated after the first 6 weeks. One hundred patients completed the 36-week study. In all phases of the study, epoetin beta was shown to produce a consistent, sustained increase in hemoglobin (baseline, 7.1 +/- 0.1 to 10.5 +/- 0.2 g/dL) and hematocrit (baseline, 21.5 to 32.7%), which virtually eliminated the need for packed red blood cell transfusions. Reticulocyte counts rose initially in response to epoetin beta and stabilized at levels higher than baseline throughout the remainder of the study period (baseline, 1.7 to 2.5%). The placebo group showed no change in these parameters during the double-blind period. Similar patterns of response were seen in the original placebo group after crossover to active drug (mean hemoglobin increase, 2.6 +/- 0.5).(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia↗
PubMed1991

Role of the sodium ion in acute renal failure.

Acute renal failure (ARF), an abrupt decline in renal function in its simplest terms, continues to elude precise pathophysiologic definition in human as well as experimental models. In the setting of ischemic or toxic renal injury, the role of sodium chloride as the major constituent of extracellular fluid volume (ECFV) is critically important in the maintenance of renal blood flow. Renal perfusion can be severely curtailed in states of ECFV depletion by activation of the renin-angiotensin axis leading to profound intrarenal hemodynamic alterations. This review will discuss evidence for the role of sodium chloride in the pathogenesis and modification of ischemic and toxic ARF. Much of the data arises from studies in experimental animal models of human disease. The results of clinical studies will be emphasized when available.

Acute Kidney Injury↗
PubMed1991

Outcome of renal transplantation at Oregon Health Sciences University: 1982 to 1990.

1. Graft survival increased over the 4 periods between 1982 and 1990 (82-84, 85-86, 87-88, 89-90). The largest increase was in the 89-90 period. 2. Immunosuppression was the key to improved outcome. Cadaveric graft recipients given OKT3 induction plus triple therapy with cyclosporine, azathioprine, and prednisone had significantly better graft survival compared with all other drug combinations. Other factors were improved patient selection, donor management, and outpatient care. 3. Mean serum creatinine levels did not change after cyclosporine was introduced for immunosuppression. The mean serum creatinine level was approximately 1.7 mg/dl at 3 months, 6 months, and 12 months post-transplantation in all 4 periods. 4. Living-related donor outcome was significantly better than cadaveric donor outcome. Half-life for 2-haplotype-matched kidneys was 37 years compared with 12 years for 1-haplotype matches and 6.5 years for cadaveric kidneys. 5. Immediate function and a rejection-free first month were both associated with significantly improved graft survival. 6. Neither peak PRA nor graft number (1st vs regraft) correlated with graft survival. Highly sensitized (PRA greater than 50%) patients and regrafted patients fared as well as less sensitized (PRA less than or equal to 50%) and first graft recipients. This outcome was attributed to a sensitive crossmatch. Because of the crossmatch, highly sensitized patients received much better HLA matches. 7. The incidence of early rejection and delayed function declined significantly between the earliest and latest periods. Improved immunosuppression, donor management, and renal preservation were cited as contributing factors.

Actuarial Analysis↗
PubMed1991

Side effects of erythropoietin therapy.

Recombinant erythropoietin is usually associated with marked improvement in physiological and psychological well-being. Adverse effects are unusual. In this report, the unusual occurrence of seizures, increased clotting, and influenza-like syndromes is reviewed. Emphasis is given to adverse effects noted in the few available placebo-controlled studies.

Anemia↗
PubMed1990

Renal effects of cyclosporine.

Renal dysfunction is a frequent consequence of cyclosporine administration, even when cyclosporine blood concentrations are maintained within proper therapeutic levels. As dermatologic indications for this compound expand, it is important for clinicians to understand the relevant pharmacology and physiology that underlie cyclosporine-induced renal dysfunction. This article reviews the clinical pharmacology of cyclosporine, the principles of renal function testing, and the clinical manifestations of this drug's effects on the kidney. Sudden declines in kidney function, long-term cyclosporine nephrotoxicity, hemolytic-uremic syndrome, and hypertension are discussed from a clinical and experimental standpoint. Finally, practical suggestions are provided to aid the dermatologist in managing cyclosporine-treated patients.

Creatinine↗
PubMed1990

Geriatric pharmacokinetics and the kidney.

The general population is aging and, as a result, drugs are increasingly prescribed for a variety of medical conditions in a group of patients with multiple physiologic and pharmacokinetic abnormalities. The present report summarizes principles of prescribing for the elderly, especially those related to the decline in renal function that frequently occurs.

Absorption↗
PubMed1990

Low-level lead exposure, blood pressure, and calcium metabolism.

Previous research has shown an association of both blood lead and dietary calcium with blood pressure (BP) in populations. We examined the relationship between blood levels and BP, the effect of calcium supplementation on blood lead, and whether the reported antihypertensive effect of calcium supplementation was related to any observed change in blood lead. BP was measured on four occasions, 1 week apart in 251 subjects. During this period, blood lead and erythrocyte protoporphyrin (EPP) levels were measured, as well as markers of calcium metabolism. In an intervention period, 142 patients were assigned to receive 1 g of calcium per day as calcium carbonate for 12 weeks; at the end of this period, blood lead and EPP were remeasured. In males, blood lead levels were significantly, directly related to BP; a 0.48 mumol/dL (10 micrograms/dL) increase in blood lead concentration was associated with a 5 mm Hg increase in systolic pressure. There was no relationship of blood lead levels to BP in females. EPP was unrelated to BP. Similarly, there was no relationship of blood lead levels to markers of calcium metabolism. With calcium supplementation, blood lead and EPP levels did not change significantly. We conclude that it is unlikely that modification of lead status explains any effects of calcium supplementation on BP.

Adult↗
PubMed1990

Effects of hyperglycemia and mannitol infusions on renal hemodynamics in normal subjects.

Early diabetes mellitus is characterized by an increase in glomerular filtration rate and effective renal plasma flow which may initiate and potentiate glomerular injury which ultimately results in diabetic nephropathy. To investigate the role of hyperglycemia per se in mediating these hemodynamic changes, eight healthy adults had inulin clearance, creatinine clearance, and para-aminohippurate (PAH) clearance after steady state conditions of hyperglycemia were achieved (549 +/- 86). Clearances were repeated during equivalent osmotic diuresis with Mannitol. Euvolemia was maintained by quantitative fluid and electrolyte replacement of urinary losses. Mean inulin clearances were 87 +/- 6, 87 +/- 5, and 81 +/- 4 ml/min during control, glucose, and mannitol periods (p = ns). Creatinine clearance overestimated inulin clearance by 15-32% but there were no differences between control glucose and mannitol periods. PAH clearance fell from control values of 595 +/- 29 to 340 +/- 22 ml/min during hyperglycemia (p less than .05). During osmotic diuresis with mannitol PAH, clearance rose to control values. In vitro studies excluded the possibility that conjugation between glucose and PAH can explain the clearance results. These results in normal subjects documenting renal vasoconstriction with hyperglycemia are of particular interest in view of recent experimental data suggesting that failure to vasoconstrict characterizes the hemodynamics of early diabetes.

Adult↗
PubMed1990

The failure of nisoldipine to prevent the hypertensive response to cyclosporine A infusion in sheep.

Hypertension and nephrotoxicity are major clinical problems associated with cyclosporine A administration. Sheep rapidly develop hypertension after intravenous administration of cyclosporine A at 6 mg/kg per day over 5 days, and this is associated with a rise in peripheral resistance. Nephrotoxicity is not a feature of cyclosporine A-induced hypertension in this species. This study reports the use of nisoldipine to investigate the role of Ca2(+)-induced smooth muscle contraction in cyclosporine A-induced hypertension in conscious sheep. After 3 control days, nisoldipine at 24 mg/day was infused intravenously alone for 24h (E1), followed by 5 days of nisoldipine plus cyclosporine A (6 mg/kg per day; E2-E6). After 24 h of nisoldipine alone, mean arterial pressure (MAP) was unchanged, heart rate rose from a control value of 60 +/- 2 beats/min to 102 +/- 9 beats/min (P less than or equal to 0.001), calculated total peripheral resistance (CTPR) fell from 15.8 +/- 0.5 to 11.7 +/- 0.5 mmHg/l per min (P less than or equal to 0.001) and stroke volume fell from 73 +/- 4 ml/beat to 60 +/- 5 ml/beat (P less than or equal to 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Cyclosporine-induced hypertension in sheep. The role of thromboxanes.

Thromboxanes have been implicated in the CsA-induced hemodynamic changes and impairment in renal function in humans and in rats. We have previously shown that administration of intravenous CsA to sheep for 5 days at 12 mg/kg/day produces a hypertension that is resistance mediated and independent of nephrotoxicity. In this study we used a thromboxane synthetase inhibitor, U63,557A, to examine the role of thromboxanes in the CsA-induced hypertension in the sheep. The thromboxane synthetase inhibitor had no effect on blood pressure in normotensive sheep. Serum thromboxane levels were not elevated with CsA, and the inhibitor had a minimal effect on blood pressure during CsA treatment, suggesting that thromboxanes are not a major contributor to the rise in blood pressure seen in the sheep. A study of the dose-response relationship for CsA at 3, 6, and 24 mg/kg/day for 5 days indicated that maximal blood pressure responses were attained with 6 mg/kg/day.

Animals↗
PubMed1990

Nephrotoxicity of common drugs used by urologists.

Many clinically popular drugs, such as aminoglycoside antibiotics, amphotericin B, radiographic contrast media, analgesics, platinum-based cancer chemotherapy, and cyclosporine, can cause deterioration of kidney function even when the dose has been adjusted properly for renal insufficiency. The authors review the pathophysiologic mechanisms of nephrotoxicity of these drugs and prevention and treatment strategies.

Aminoglycosides↗