Some questions on nephrotoxicity.
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Animals↗
Biomedical subjects
G H Mudge
Publications and source records attributed to G H Mudge.
Biliary and urinary excretion of iopanoic acid in the dog.
The urinary and biliary excretion of iopanonic acid was studied in anesthetized dogs infused with sodium iopanoate and trace amounts of 125I-iopanoic acid to provide a wide range of plasma concentrations. Samples of kidney and liver were also analyzed for total radioactivity. The sole excretory product in urine and bile was the glucuronide conjugate. The secretory biliary Tm for for iopanoic acid varied between experiments. Biliary concentration far exceeded that of plasma and liver/plasma ratios were all greater than unity. The fractional rate of urinary excretion varied 1-80% and was strongly correlated with hepatic function, e.g. the rate of bile flow. The data are interpreted to indicate that, depending on the rate of bile flow, the glucuronide formed in the liver is partioned between bile and blood, the latter for urinary excretion. This mechanism is discussed in relation to cholecystographic visualization and to the problem of nephrotoxicity.
Animals↗
Effect of choleretics on biliary and urinary excretion of cholecystographic agents.
Two choleretic agents, taurocholate and cinchophen, were studied in the dog to determine their effect on both the biliary and urinary excretion of two related cholecystographic agents, iopanoic acid and iophenoxic acid. Liver concentrations were determined on biopsies. Trace amounts of radioactively labeled compounds were used for measurements. The effect of the choleretic agent was specific for the cholecystographic compound. Taurocholate increased both biliary and urinary excretion of iopanoic acid and decreased its intrahepatic level, but had no effect on iophenoxic acid. Cinchophen had no effect on iopanoic acid but increased both biliary and urinary excretion of iophenoxic acid. When examined against a pre-existing high rate of bile flow, the active choleretic increased, rather than decreased, the biliary concentration of the cholecystographic compound. The increased excretion in both bile and urine cannot be attributed simply to the lessened concentration gradient from plasma to bile, as proposed by others. The data are consistent with a direct action of the choleretic agent on hepatic mechanisms, either to decrease intracellular binding or to alter the characteristics of transport.
Animals↗
The maximal urinary concentration of diatrizoate.
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Acute Kidney Injury↗
Cholecystographic agents and drug binding to plasma albumin.
These studies have identified two separate sites for drug binding to human serum albumin (HSA). They began in an attempt to explain the persistence in plasma of iophenoxic acid, a now abandoned oral cholecystographic agent. This is identical to iopanoic acid save for -OH instead of -NH2 in the 3 position. Iophenoxate has a half-life in man of about three years, compared to several weeks for iopanoate. Both drugs are reversibly bound to HSA with high affinity. Attempts to determine the exact extent of binding were complicated by drug-radiolysis of 125I-labeled contrast agent. Once this was overcome, reproducible data were obtained, which yielded KD at the site of highest affinity of 0.15 microM for iopanoate and 0.013 microM for iophenoxic acid, thus making the latter the most tightly bound of known drugs. We then studied competitive binding, measuring free and bound drug and competitor. From analysis by computerized programs, iophenoxate binds most firmly at site I, iopanoate most firmly at the site II, both showing competition with each other. The findings are in agreement with Sudlow, Birkett, and Wade, who identified separate binding sites with completely different techniques. They have identified a large number of commonly used drugs that bind specifically to one site or the other. It is clear that drug binding to HSA will in the future be considered in reference to specific sites. It is not known at present to what extent the cholecystographic agents may participate in drug-drug interactions related to binding to HSA. The available data will be reviewed.
Binding Sites↗
Cyclosporine A and prednisone-associated osteoporosis in heart transplant recipients.
Immunosuppressive therapy with cyclosporine A or prednisone produces bone loss in some animal models. Although we have clinically observed osteoporotic fractures in our heart recipients, the effects of cyclosporine and prednisone on bone density in transplant populations has not been fully elucidated. This study was undertaken to examine indexes of mineral metabolism and bone mineral density (BMD) in heart transplant recipients referred for evaluation of possible bone disease. Twenty of 93 patients who underwent heart transplantation at our institution were evaluated for osteoporosis. Sixteen of these patients (eight men; eight women) were included in this cross-sectional study (two patients were excluded because of hyperparathyroidism, and two patients were excluded because severe fractures prevented BMD from being measured). The mean age of the heart transplant recipients was 52.4 +/- 2.2 years, and the study was conducted a mean of 33.4 +/- 4.6 (men) and 19.0 +/- 7.0 (women) months after heart transplantation. Forty-four percent of these heart transplant recipients were seen clinically with fractures. Biochemical tests of skeletal homeostasis and BMD measurements with dual energy x-ray absorptiometry were performed. In male and female patients, the indexes of mineral metabolism showed (mean +/- sem) osteocalcin levels of 9.60 +/- 2.3 micrograms/L and 9.46 +/- 1.9 micrograms/L (normal: men, 6.39 +/- 0.69 micrograms/L; women, 5.87 +/- 0.71 micrograms/L) and intact parathyroid hormone levels of 48.8 +/- 10.3 ng/L and 63.4 +/- 10.7 ng/L (normal: men, 26.8 +/- 3.3 ng/L; women, 30.7 +/- 2.1 ng/L), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Bone Density↗
Endothelial dysfunction in the development and detection of transplant coronary artery disease.
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Acetylcholine↗
Results of heart transplantation for active lymphocytic myocarditis.
To determine whether the heart-specific immunoreactivity associated with active myocarditis affects outcome after heart transplantation, we retrospectively analyzed the outcome of 12 patients with active lymphocytic myocarditis in their explanted native hearts identified by the Registry of the International Society for Heart Transplantation. The patients were 38 +/- 10 years of age and predominantly female (75%). In nine patients (75%), endomyocardial biopsy showed active myocarditis before transplant; eight of these patients also received immunosuppression before transplant. Recipient hemodynamic study before transplantation demonstrated an ejection fraction of 0.18 +/- 0.06, cardiac index of 1.7 +/- 0.4 L/min/m2, pulmonary artery pressure of 41 +/- 6/23 +/- 6 mm Hg, and mean pulmonary capillary wedge pressure of 30 +/- 5 mm Hg. Left ventricular end-diastolic dimension by echocardiography was 6.0 +/- 1.4 cm. Four of the patients were dependent on intravenous inotropes, and six required mechanical assistance. Over a 36-month follow-up period, 2.9 +/- 2.4 episodes of rejection occurred per patient. Sixty percent of the first episodes occurred within 2 weeks of transplantation. These patients experienced a 2.2 +/- 1.1-fold increase in rejection compared with institutional average rejection rates. Survival was significantly shorter than that of age-matched or female control subjects. This study is limited by its retrospective nature and the unusual pretransplant characteristics of the subjects. It indicates that active myocarditis may predispose patients to early severe rejection and a high mortality rate after heart transplantation.
Adult↗
Binding of iophenoxate and iopanoate to human serum albumin.
Determination of the binding affinities of 125I-labeled cholecystographic agents to human serum albumin by ultrafiltration techniques is complicated by the appearance of radiochemical impurities resulting from radiolysis of the parent compound. With labeled compounds purified daily by two extractions through chloroform, iophenoxic acid has an extremely high binding affinity. The dissociation constant (K) is 0.013 micronM for iophenoxate, compared to 0.15 micronM for iopanoate, its close analogue. However, at the weaker sites, iophenoxic acid is less strongly bound than iopanoate. The exceptionally high affinity of iophenoxate for a single site of serum albumin appears to underlie its unusual persistence in plasma. Binding in vivo is reversible and not covalent in nature. The choleretic compounds cinchophen and taurocholate have differential effects on the biliary excretion of iophenoxate and iopanoate. This cannot be attributed to selective inhibition of binding to plasma protein.
Crystallization↗
Competition for binding to multiple sites of human serum albumin for cholecystographic agents and sulfobromophthalein.
The binding of two cholecystographic agents, iophenoxate and iopanoate, to human serum albumin was studied with 11 putative competitors; the results were qualitatively consistent with competitive binding to common sites. A more precise analysis of competition was achieved with four pairs of compounds for which the free and bound concentration of each was determined. The results were analyzed by a computer program and the dissociation constants calculated for both binder and competitor at specified sites on albumin. With numbering based on the rank order of dissociation constants for iophenoxate, the highest binding of the four compounds occurs at different sites: iophenoxate at site I; iopanoate at site II, sulfobromophthalein at site III; and bromphenol blue at site II. For a given compound, there is close agreement in the calculated affinities at different sites regardless of the competitor.
Binding Sites↗
Renal excretion of iodipamide. Comparative study in the dog and rabbit.
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Aminohippuric Acids↗
Formation and disposition of the minor metabolites of acetaminophen in the hamster.
The urinary metabolites of acetaminophen and N-hydroxyacetaminophen were studied in the hamster over a wide dose range and with pretreatments designed to modify drug metabolism. Attention was focused on the origin and disposition of the minor metabolites. The sum of the 3-thio adducts, rather than just the 3-mercapturic adduct, is considered the better index of the formation of the reactive immediate precursor, presumably N-acetyl-p-benzoquinoneimine. At low dosage this amounts to 33% of the administered dose in this species. There is a major contribution from the 3-methylthio adduct, the magnitude of which has not been previously recognized. The 3-methylthio and the 3-methylsulfoxide derivates of acetaminophen are secondarily derived from the 3-glutathione adduct within the enterohepatic circulation, as indicated by their late appearance in the urine, the effect of common bile duct ligation and the metabolism of the minor metabolites when they themselves are administered. Following the administration of N-hydroxyacetaminophen this was excreted in the urine along with its phenolic conjugates, but no urinary N-hydroxyacetaminophen was detectable after the administration of acetaminophen itself. Of particular interest to the pathogenesis of analgesic nephropathy was the detection in the urine of small amounts of p-aminophenol, a known nephrotoxic agent, following dosage with acetaminophen. This metabolite has not been previously detected.
Acetaminophen↗
Changing patterns in donor and recipient risk: a 10-year evolution in one heart transplant center.
BACKGROUND: Expansion of the donor pool and liberalization of recipient criteria have occurred since the introduction of cyclosporine for heart transplantation. METHODS: We sought to evaluate the impact of these changes on outcome during a 10-year period in one program. A total of 251 transplantations were retrospectively reviewed and divided into two periods (1984 to 1989 and 1990 to 1994). RESULTS: In the latter period, there were increases in donor and recipient age, degree of weight mismatch, ischemic time, bypass time, and severity of illness in the recipient before transplantation as judged by status at the time of transplantation and preoperative requirements for pharmacologic or mechanical support. Despite these changes, time to hospital discharge decreased and a trend to improved survival was seen with the use of Kaplan-Meier analysis. CONCLUSIONS: These findings suggest that improvements in perioperative and posttransplantation care have permitted a safe expansion of both the donor pool and recipient criteria for transplantation.
Adult↗
Role of panel-reactive antibody cross-reactivity in predicting survival after orthotopic heart transplantation.
To test the hypothesis that elevated preformed circulating antibody levels, as measured by panel-reactive antibody levels, predict survival after orthotopic heart transplantation, we analyzed 120 consecutive patients undergoing heart transplantation at the Brigham and Women's Hospital in a retrospective, chart-review format. Prospective, donor-specific lymphocyte crossmatches were performed in all patients with a panel-reactive antibody level of 10% or greater. Both the peak pretransplantation panel-reactive antibody level and the panel-reactive antibody level obtained on the day of transplantation were analyzed with respect to the end points of the number of acute rejection episodes, presence of coronary artery disease, and overall survival after transplantation. Patients with a panel-reactive antibody level on the day of transplantation of 25% or greater, despite a negative prospective donor-specific lymphocyte crossmatch, demonstrated a trend toward reduced actuarial long-term survival compared with patients with panel-reactive antibody values less than 25% (p < 0.05). Panel-reactive antibody levels were not predictive of the number of acute rejection episodes, early (< 60 days) versus late (> or = 60 days) death, or the development of graft coronary artery disease. No episodes of hyperacute rejection were observed, even in six patients with a positive retrospective donor-specific lymphocyte crossmatch. In conclusion, an elevated panel-reactive antibody value of 25% or greater at the time of heart transplantation may be a risk factor for decreased long-term survival. A trend toward an increased risk of death caused by rejection was also observed.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Sinoatrial and atrioventricular block caused by intracoronary infusion of adenosine early after heart transplantation.
Intracoronary adenosine was infused in 22 patients early (less than 2 months) after heart transplantation to study coronary flow reserve in the left anterior descending artery. Potentially serious bradycardia requiring discontinuation of the infusion occurred in three patients. This complication had not been noted when adenosine was given to 84 patients with at least 1 year after transplantation. Newly transplanted hearts may therefore have increased susceptibility to the bradycardic action of adenosine, which should be used with caution in this population.
Adenosine↗