Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035078 (renal failure)
 31,970 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro binding of phenylbutazone and phenytoin was studied in serum in tissue homogenates, in tissue slices and in blood cells of rabbits with acute renal failure induced by uranyl nitrate. For phenylbutazone serum binding was decreased in uraemic rabbits, while the binding in homogenates of kidneys and liver was increased. For phenytoin binding in serum and in homogenates and slices of kidneys was decreased in uraemic rabbits. Binding of phenylbutazone and phenytoin to blood cells was not significantly changed in uraemic rabbits. The changes in tissue binding found are small and are only significant for liver and kidney which represent a small fraction of total body mass. Although the methodology for measurement of tissue binding is not entirely satisfactory, we think we can conclude that these changes probably contribute only to a minor degree to the increase of the volume of distribution found for these drugs in renal failure as already suggested by our in vivo data in the preceding paper.
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PMID:Binding of drugs in serum, blood cells and tissues of rabbits with experimental acute renal failure. 720 96

Renal dysfunction can have substantial effects on the pharmacokinetics and pharmacodynamics of drugs. A wide variety of animal models have been developed in an attempt to mimic conditions seen in human renal failure. In reality, no single animal model would be completely satisfactory because the etiology and development of renal failure are diverse. During recent years injection of uranyl nitrate has been found to be the most effective and easiest method to produce renal dysfunction in laboratory animals. Changes over the last 10 years in government regulations on the production and use of radioactive substances make the compound less available. There is, therefore, a need for a more accessible compound comparable to uranyl nitrate as an inducer of renal failure. The present study compares the effects of another known nephrotoxin, cisplatin, with uranyl nitrate in the rat. Cisplatin was chosen because of its ability to produce kidney damage and its identical site and mechanism of action on the kidneys as uranyl nitrate. In the present study, rats were given different i.v. doses of uranyl nitrate or cisplatin dissolved in 0.9% of saline solution. The effects of nephrotoxins were evaluated on the basis of changes in body weight, creatinine and blood urea nitrogen (BUN) concentrations. It was found that the degree of renal damage produced by uranyl nitrate and cisplatin is a function of the administered dose. With increasing dose there is evidence of more severe kidney damage, as measured by substantially increased plasma concentrations of creatinine and BUN. The time required to return to normal creatinine and BUN concentrations was also a function of dose. Furthermore, plasma alanine aminotransferase (ALT) activity was measured as an index of hepatocellular damage. The ALT test showed that a single dose does not affect the liver function. From dose-response curves a dose of 4 mg/kg body weight of uranyl nitrate or cisplatin was chosen to produce acute renal failure in animals for pharmacokinetic study of barbital. Barbital (100 mg/kg) was administered on the fifth day (the day of maximum renal dysfunction) to uranyl nitrate, cisplatin-treated and control rats. The elimination rate constant (k), elimination half life (t1/2), volume of distribution at steady state (Vss), total (CLt) and renal clearance (CLr) were significantly different in treated groups of rats from control, however no such difference was detected between uranyl nitrate and cisplatin-treated group of rats. In short, cisplatin is comparable to uranyl nitrate in producing renal failure in the rat and can be considered a suitable alternative.
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PMID:A comparative study of uranyl nitrate and cisplatin-induced renal failure in rat. 773 34

The processes of uranium extraction, purification, and manufacture involve the risk of chemical intoxication. Acute uranium poisoning elicits renal failure which in turn may lead to death. Great efforts have been put into the search for a protective agent for acute uranium poisoning. Several chelating agents such as EDTA, Tiron, DTPA, or aminosalicylic acid have been experimentally assayed. However, even when these agents are able to reduce the mortality none of them achieve 100% survival. We herein present the use of EHBP to prevent mortality due to uranium poisoning. Rats weighing 14 g were employed in two different experiments: A) The surviving animals were killed on the 60th day; and B) The animals were killed on the 9th day. In both experiments 4 groups were considered: 1. untreated control; 2. one intraperitoneal (IP) injection of uranyl nitrate (2 mg kg-1 of body weight); 3. 1 IP injection of EHBP (10 mg kg-1 of body weight); and 4. treatments 2 and 3 combined. In both experiments 50% of the animals in group 2 died on the eighth day. All the animals of the other groups were alive at the end of the experiment. Histological analysis of the kidneys of the animals of experiment B revealed renal damage in the exposed animals, whereas no structural alterations were detected in the kidneys of the other three groups, including those given uranyl nitrate and treated with EHBP. These results show the efficiency of only one injection of EHBP to avoid renal damage and to counteract the mortality due to uranium poisoning with a success rate of 100%.
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PMID:Lethality due to uranium poisoning is prevented by ethane-1-hydroxy-1,1-biphosphonate (EHBP). 817 60

The effect of oral administration of activated charcoal on total body clearance of vancomycin administered intravenously (7.5 mg/kg) has been studied in normal rabbits and rabbits with induced renal failure. Gastric intubation of a single dose (10 g) of activated charcoal to normal rabbits did not produce a statistically significant effect on any pharmacokinetic parameter for vancomycin. The mean vancomycin clearances were (mean +/- s.d.) 80.82 +/- 6.8 and 75.24 +/- 9.61 ml/h/kg with and without activated charcoal administration, respectively. To examine whether renal failure would influence the effect of activated charcoal and enhance the systemic clearance of vancomycin, uranyl nitrate was used (0.75 mg/kg, i.v.) to induce acute renal failure in rabbits. The derived pharmacokinetic parameters of vancomycin were consistent with renal failure. No significant differences were observed in any of the calculated pharmacokinetic parameters between the control and charcoal treated rabbits. The lack of effect may be attributed to the large molecular weight of vancomycin.
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PMID:Effect of oral activated charcoal on vancomycin clearance in rabbits with acute renal failure. 822 36

Nitric oxide derived from vascular endothelium is a potent vasodilator that plays a key role in the homeostasis of blood pressure. Because cirrhotic patients tend to have low arterial pressure, we measured in 51 patients and 10 control subjects serum nitrite and nitrate levels as an index of in vivo nitric oxide generation. We also measured plasma endotoxin, a substance frequently increased in cirrhotic patients and known to induce nitric oxide synthesis. Cirrhotic patients showed significant increases in serum nitrite/nitrate and plasma endotoxin compared with controls. Values were particularly increased in patients with decompensated cirrhosis, as manifested by ascites with or without functional kidney failure. High serum nitrite/nitrate levels were associated with high plasma renin activity, high aldosterone and antidiuretic hormone levels and low urinary excretion of sodium. In addition, serum nitrite/nitrate levels significantly correlated with endotoxemia. Oral administration of colistin to 15 cirrhotic patients reduced significantly plasma endotoxin levels (p < 0.01) and serum nitrite/nitrate levels (p < 0.05). Because endotoxin enhances the expression of inducible nitric oxide synthase, our results suggest that circulating endotoxin in cirrhosis is responsible for excessive synthesis and release of nitric oxide by the vasculature. These findings might explain the hemodynamic dysfunction seen in cirrhotic patients.
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PMID:Increased serum nitrite and nitrate levels in patients with cirrhosis: relationship to endotoxemia. 822 20

The pharmacokinetics of R- and S-atenolol after intravenous administration of racemic atenolol were studied in 3-, 12- and 24-month-old rats and in 3-month-old rats with renal failure induced by uranyl nitrate. In all age groups, the area under the plasma concentration-time curves is higher for R- than for S-atenolol; volume of distribution, total clearance and renal clearance are lower for R-atenolol than for S-atenolol, but the differences are small. In function of age there is for both enantiomers a significant increase in AUC, due, at least in part, to a decreased renal clearance; the effect of aging is not stereoselective. In rats with renal failure, the AUC of both enantiomers increases, due mainly to a decrease in renal clearance, but to a lesser degree also to a decrease in nonrenal clearance. For both enantiomers, the volume of distribution decreases and the half-life increases in the uraemic rats. The total amount of both enantiomers excreted in the urine is decreased in the rats with renal failure. There are no stereoselective effects of treatment of the rats with uranyl nitrate.
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PMID:Stereoselective pharmacokinetics of atenolol in the rat: influence of aging and of renal failure. 846 31

Many acyl glucuronides are labile, reactive and form covalent adducts with proteins. In the present experiment, the stability of salicyl acyl glucuronide (SAG), its reactivity with serum albumin in vitro and the influence of renal failure in rats on the disposition of SAG and covalent binding of salicylate (SA) to rat plasma proteins were investigated. In vitro studies showed that SAG was hydrolyzed to SA or undergoes isomerization to positional isomers. The half-life of SAG was 1.3 hr in 0.15 M phosphate buffer at pH 7.4 and 37 degrees C, but the stability of its isomers was much greater with an apparent half-life of 19 hr. Incubation of SAG in solutions of human serum albumin revealed the formation of covalent adducts with the protein, with maximal binding of 2.8% of total SA equivalents added to the solution. For in vivo studies, one group of rats was administered 5 mg/kg of uranyl nitrate i.p. to induce renal failure. After administration of 100 mg/kg of SA i.v., the AUC 0-26 hr of SAG in rats with renal failure was 9 times higher than that observed in control rats. The apparent clearance of SA decreased from 64 +/- 21 ml/hr in control rats 28 +/- 8.7 ml/hr in rats with renal failure. The level of SA covalent adducts with plasma proteins reached about 0.5 ng/mg of protein in control rats, whereas in rats with renal failure the binding was increased significantly and achieved an average peak concentration of 18 ng/mg of protein when measured 26 hr after dosing. The data indicate that reactive SAG can accumulate in renal failure which then increases covalent addition of SA to proteins. Such binding may have a role in enhancing the potential for toxicity of acidic drugs such as SA in renal disease.
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PMID:Influence of renal failure in rats on the disposition of salicyl acyl glucuronide and covalent binding of salicylate to plasma proteins. 876 61

Use of ibuprofen in patients with asymptomatic renal failure is known to produce acute renal toxicity. One of the manifestations is interstitial nephritis of which the pathogenic mechanism remains unclear. In the present study, this nephrotoxic syndrome was induced in rabbits by giving a single dose of uranyl nitrate, followed by consecutive doses of ibuprofen. This animal model thus allowed the assessment of renal functional and pathological changes associated with ibuprofen use in renal insufficiency. In these rabbits, the major abnormality appeared to be confined to the tubulointerstitial compartment. Microscopic examinations of the renal necropsy specimens showed tubular necrosis and interstitial lymphocytic infiltration. The histological finding of lymphocytic aggregation suggests that this nephrotoxic effect stems from a cytotoxic immune reaction in the interstitium. Moreover, levels of renal 2-arylpropionyl-CoA epimerase, a key enzyme involved in the metabolic inversion of ibuprofen, showed a significant reduction, which may result from the massive destruction of the tubular cells in these animals. These results support the premise that renal insufficiency is a prerequisite factor for ibuprofen-induced interstitial nephritis.
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PMID:Pathological and biochemical modifications of renal function in ibuprofen-induced interstitial nephritis. 882 Apr 99

Increased sympathetic nervous system (SNS) activity plays a role in the genesis of hypertension in rats with chronic renal failure (CRF). Because nitric oxide (NO) modulates the activity of the SNS, a deficit of NO synthesis could be responsible for the increased SNS activity in these animals. In the present study, we evaluated the effects of L-arginine and L-NAME on blood pressure and SNS activity-in Sprague Dawley 5/6 nephrectomized or sham-operated rats. SNS activity was determined by measuring norepinephrine turnover rate in several brain nuclei involved in the regulation of blood pressure. In the same brain nuclei, we measured NO content and nitric oxide synthase (NOS) gene expression by semiquantitative measurements of NOS mRNA reverse transcription polymerase chain reaction. In CRF rats, norepinephrine turnover rate was increased in the posterior hypothalamic nuclei, locus coeruleus, paraventricular nuclei, and the rostral ventral medulla, whereas NOS mRNA gene expression and NO2/NO3 content were increased in all brain nuclei tested. L-NAME increased blood pressure and NE turnover rate in several brain nuclei of both control and 5/6 nephrectomized rats. In CRF rats, a significant relationship was present between the percent increment in NOS mRNA gene expression related to the renal failure, and the percent increase in norepinephrine turnover rate caused by L-NAME. This suggests that endogenous NO may partially inhibit the activity of the SNS in brain nuclei involved in the neurogenic regulation of blood pressure, and this inhibition is enhanced in CRF rats. In summary, the increase in SNS activity in the posterior hypothalamic nuclei and in the locus coeruleus of CRF rats is partially mitigated by increased local expression of NOS m-RNA.
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PMID:Nitric oxide (NO) modulates the neurogenic control of blood pressure in rats with chronic renal failure (CRF). 902 90

The production of both nitric oxide (NO) and superoxide increases in septic shock. The cogeneration of these molecules is known to yield peroxynitrite, which preferentially nitrates tyrosine residues of protein and non-protein origins. We present evidence of peroxynitrite production in septic shock by measuring plasma nitrotyrosine. The nitrotyrosine was measured by an HPLC C-18 reverse-phase column and ultraviolet detector in chronic renal failure patients with or without septic shock, and in healthy volunteers. Plasma nitrite + nitrate (NOx) was also measured to evaluate NO production. Nitrotyrosine was selected as an index for production of peroxynitrite because the direct measurement of peroxynitrite in vivo is difficult. Patients with renal failure were selected in order to minimize nitrotyrosine excretion through the kidney. Plasma nitrotyrosine levels were not detectable in volunteers, 28.0 +/- 12.3 microM (1.6 +/- 1.1% of total tyrosine) in renal failure patients without septic shock, and 118.2 +/- 22.0 microM (5.5 +/- 1.2% of total tyrosine) in patients with septic shock. NOx levels were also higher in patients with septic shock than in patients without septic shock (173.9 +/- 104.7 vs. 75.6 +/- 19.1 microM). Although renal failure itself increases plasma concentrations of both molecules, the higher levels in patients with septic shock suggest that peroxynitrite is generated and the nitration of tyrosine residues is increased in this disease.
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PMID:Clinical evidence of peroxynitrite formation in chronic renal failure patients with septic shock. 911 44


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