Chronic pancreatitis and obstructive jaundice from a round-cell tumor involving the pancreas.
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Carcinoma, Small Cell↗
Biomedical subjects
R E Kane
Publications and source records attributed to R E Kane.
Sulfation and glucuronidation of acetaminophen by human hepatocytes cultured on Matrigel and type 1 collagen reproduces conjugation in vivo.
UNLABELLED: Our previous studies demonstrated marked sex differences in the metabolism of acetaminophen in rats both in vivo and in hepatocyte culture. This study examined the sex differences in human acetaminophen metabolism, and the ability to reproduce in vivo metabolism in human hepatocyte cultured on Matrigel vs. type 1 collagen. Human hepatocytes were isolated by collagenase perfusion of 10-15 g biopsies of patients without liver disease undergoing elective abdominal operations (8 females, age 41.3 +/- 19.3 years; 6 males, age 47.7 +/- 21.3 years). Postoperatively, patients were given 1 g of acetaminophen orally and a 24-hr urine collected to determine the metabolic fate. There were no sex differences in acetaminophen conjugation in vivo, nor in the hepatic acetaminophen sulfotransferase activities as observed in the rodents. Hepatocytes were cultured with acetaminophen (0, 150, 250, 500, and 1000 microM) on Matrigel and type I collagen. Acetaminophen glucuronidation predominated over acetaminophen sulfation just as in vivo without sex differences on days 1 and 2 in culture. By days 3 and 4, however, glucuronidation by female hepatocytes became enhanced compared with males. With increasing acetaminophen concentration (dose), there was a linear increase in sulfate and glucuronide conjugation without saturation of either pathway as observed in the rat. CONCLUSIONS: 1) there are no sex differences in acetaminophen metabolism or acetaminophen sulfotransferase activity as observed in the rat; 2) acetaminophen sulfation and glucuronidation by cultured human hepatocytes in vitro replicated in vivo metabolism on matrigel and type 1 collagen for the first 2 days in culture; and 3) glucuronidation became enhanced with time in the culture of female, but not male hepatocytes.
Acetaminophen↗
Correlation between venous and capillary blood samples for cyclosporine monitoring in pediatric liver transplant patients.
Venipuncture has traditionally been required to monitor serum cyclosporine levels. This is a difficult if not impossible task in pediatric patients. Capillary blood sampling has eliminated the need for venous access in the majority pediatric laboratory investigations. Although the practice of capillary sampling for cyclosporine monitoring is discouraged, there has never been any investigation into the reliability of this method. Thus, we compared 18 capillary cyclosporine levels from 4 pediatric liver transplant patients to simultaneous venipuncture serum levels. The correlation coefficient of the paired samples (range 32-1005 ng/ml) was 0.914. This excellent correlation between the two sampling methods suggests that capillary cyclosporine levels may be adequate to monitor the immunosuppression of pediatric liver transplant patients.
Capillaries↗
Acute hepatic and renal toxicity from low doses of acetaminophen in the absence of alcohol abuse or malnutrition: evidence for increased susceptibility to drug toxicity due to cardiopulmonary and renal insufficiency.
A 67-yr-old man with chronic cardiopulmonary disease exhibited severe hepatic and moderately severe renal injury after short-term ingestion of therapeutic doses of acetaminophen (1 to 3 gm/day for 3 days). Drug metabolism and other studies, performed 5 mo after recovery from the acute insult, indicated that the patient had decreased rates of hepatic metabolism of acetaminophen to its primary, nontoxic metabolites and decreased kidney function that was compromised further by acetaminophen ingestion. He also had abnormally low concentrations of hepatic and plasma reduced glutathione. Alcohol abuse and malnutrition could not be implicated in the pathogenesis of injury; rather it appeared that advancing age with chronic renal, cardiac and pulmonary insufficiency contributed to acetaminophen toxicity in this patient.
Acetaminophen↗
Severe immobilization-induced hypercalcemia in a child after liver transplantation successfully treated with pamidronate.
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Alkaline Phosphatase↗
N-acetylbenzidine-N'-glucuronidation by human, dog and rat liver.
While N-glucuronidation is an important pathway for metabolism of aromatic amines, it has not been demonstrated for N-acetylbenzidine. A glucuronide of N-acetylbenzidine was synthesized and identified by mass spectrometry as N-acetylbenzidine-N'-glucuronide. This N'-glucuronide is acid labile with a t1/2 of 4 min at pH 5.3. A similar acid lability was also observed with benzidine-N-glucuronide. The formation of N-acetylbenzidine-N'-glucuronide was assessed with liver slices and microsomes prepared from human, dog and rat. When 0.014 mM [3H]N-acetylbenzidine was incubated with human liver slices a significant amount of N-acetylbendizine-N'-glucuronide was produced (8-26% of the total radioactivity recovered). With higher concentrations of [3H]N-acetylbenzidine (1 mM) rat slices also produced N-acetylbenzidine-N'-glucuronide. However, N'-glucuronide formation was not detected with dog liver slices incubated with either 0.014 or 1 mM [3H]N-acetylbenzidine. N-Acetylbenzidine-N'-glucuronide formation was observed with microsomes prepared from human, dog and rat. To assess maximum activity four detergents were used at two concentrations. With or without detergent activation the relative amount of glucuronidation was human > > dog > rat. The rate of benzidine N-glucuronide formation was 4.3- and 1.6-fold greater than N-acetylbenzidine-N'-glucuronide in dog and rat respectively, while in human both rates were similar (1.1-fold). With or without detergent activation the relative amount of benzidine-N-glucuronide formation was human > dog > > rat. N-Glucuronidation of [3H]N,N'-diacetylbenzidine was not observed. Thus N-actylbenzidine-N'-glucuronide formation appears to be an important pathway for metabolism of N-acetylbenzidine, especially in humans. Due to their acid lability, formation of the N-glucuronides of N-acetylbenzidine and benzidine provides a mechanism for hepatic detoxification and accumulation of these carcinogens in the bladder. A new model is described illustrating the effect of N-glucuronidation and the influence of N-acetylation on arylmono- and aryldiamine-induced bladder carcinogenesis.
Animals↗
Changes in the CA 19-9 antigen and Lewis blood group with pulmonary disease severity in cystic fibrosis.
The altered carbohydrate structure of sputum from patients with cystic fibrosis (CF) has been thought to be due to the inflammatory airway response. Carcinoembryonic antigen (CEA) and CA 19-9 detect sialosylated carbohydrates in mucus. The epitope of CA 19-9 is part of the Lewis A (Le(a)) blood group antigen. Serum concentrations of CEA and CA 19-9 were determined by radioimmunoassay in 41 CF patients, aged 6-34 years; 16 were asymptomatic Outpatients, and 25 had been admitted for pulmonary exacerbations. There was no difference in CEA between groups. The CA 19-9 serum concentration was elevated in 90% of patients who had at least one of the two Lewis antigens. The CA 19-9 concentration of Inpatients with exacerbations was 2.7 times that of stable Outpatients (263 +/- 44 versus 99 +/- 13 U/mL; P less than 0.02). CA 19-9 correlated significantly with age (r = 0.35, P less than 0.05), Brasfield score (r = 0.39, P less than 0.015), pulmonary function tests, cough severity (r = 0.50, P less than 0.001) and NIH clinical score (r = 0.57, P less than 0.001). CA 19-9 concentration of Inpatients decreased by 44% from admission to discharge (302 +/- 45 to 169 +/- 39, P less than 0.02). Fourteen of 25 (56%) of the Inpatients were Le(a) positive versus only 3/15 (20%) of Outpatients who had milder lung disease (P less than 0.002). Of the Inpatients, 25% with more advanced lung disease were Le(a+b+), a rare blood group in the normal population, and one not observed in the Outpatients with milder disease.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Valproate use associated with persistent hyperammonemia and mitochondrial injury in a child with Down's syndrome.
Valproate is a commonly prescribed anticonvulsant drug that may cause potentially fatal hepatotoxicity, bone-marrow toxicity, and pancreatitis. Toxicity usually resolves, though, after discontinuation of the medication. We report a 9-year-old boy who had Down's syndrome and who developed valproate-associated bone marrow toxicity, and hepatotoxicity that persisted greater than 2 years after discontinuation of valproate therapy. Three years after starting valproate, he developed erythrocyte aplasia with a severe, normochromic, macrocytic anemia requiring several blood transfusions. Several months later while still receiving valproate, he developed progressive hyperammonemia and decreased hepatic synthetic function. The macrocytic anemia resolved and hepatic synthetic function improved after discontinuation of valproate therapy. However, hyperammonemia, steatosis, mitochondrial injury, and marked hepatic iron accumulation persisted greater than 2 years after the valproate was discontinued. The persistent hyperammonemia was responsive to lactulose therapy. A decrease in hepatic iron content by serial phlebotomies did not result in any improvement in the hyperammonemia or hepatic synthetic function. This is the first report of persistent hyperammonemia and hepatic mitochondrial injury after valproic acid therapy.
Ammonia↗
Sulfation and glucuronidation of acetaminophen by cultured hepatocytes reproducing in vivo sex-differences in conjugation on Matrigel and type 1 collagen.
The sulfate and glucuronide conjugation of acetaminophen (APAP) by hepatocytes cultured on Matrigel or type 1 collagen was compared to APAP metabolism in vivo. The metabolic fate of low (15 mg/kg), medium (125 mg/kg), and high (300 mg/kg) doses of APAP injected intraperitoneally were determined in male and female rats. Males excreted more APAP as the sulfate conjugate than females, which correlated with the twofold greater APAP sulfotransferase activity in the male vs. females (301 +/- 24 vs. 156 +/- 18 pmol.mg-1 protein.min-1). Also, as sulfate conjugation became saturated, there was a dose-related shift in APAP metabolism from sulfate to glucuronide conjugation in both sexes. After death, the livers of the same animals were perfused with collagenase and the hepatocytes cultured in modified Waymouth's medium on either Matrigel or rat-tail collagen, with various doses of APAP (0, 0.125, 0.25, 0.5, and 1.0 mM). Sex differences in APAP sulfation and glucuronidation persisted in culture for up to 4 days, with sulfation predominating in the male similar to in vivo. With increasing APAP concentration (dose), there was a saturation of sulfate conjugation and a shift to glucuronidation as observed in vivo. Sex differences in APAP sulfation and glucuronidation were no longer significant by Day 4 in culture. Sulfation, and to a lesser extent, glucuronidation, were more stable on Matrigel than collagen. We concluded that APAP metabolism of freshly isolated hepatocytes could replicate in vivo sex differences in conjugation, and that Matrigel was superior to collagen as substrate.
Acetaminophen↗
Energy and respiratory metabolism in cystic fibrosis: the influence of carbohydrate content of nutritional supplements.
The basal energy expenditure (BEE) in a group of adolescent and young adult patients with cystic fibrosis (CF) with mild lung disease was 97 +/- 6% of that predicted by the Harris-Benedict equation (which estimates BEE by age, sex, height, and weight). The BEE of a group with more severe lung disease was 117 +/- 5% of that predicted by the Harris-Benedict equation, due primarily to a 14% greater oxygen consumption (VO2) and 24% greater CO2 production (VCO2) compared with milder lung disease (p less than 0.05). The measured BEE in the patients with mild lung disease correlated well with the predicted BEE, but variably underestimated that of patients with more advanced lung disease. The influence of low carbohydrate (Pulmocare) and higher carbohydrate (Instant Breakfast) nutritional supplements on the energy and pulmonary metabolism was compared in 10 malnourished CF patients with moderate to severe lung disease. Their BEE before ingesting the supplements was 120% of that predicted by the Harris-Benedict equation. Their VCO2 increased 9-19% for the 3 h after ingesting 500 kcal/M2 of Pulmocare, and 25-30% after ingesting Instant Breakfast (p less than 0.05). The respiratory quotient (RQ) was significantly greater for Instant Breakfast than Pulmocare. The minute ventilation (VE) rose 10-13% for the 3 h after ingesting Pulmocare, versus 27-31% after ingesting Instant Breakfast, but the difference was not significant. The metabolic expenditure rose 13-16% for the 3 h after ingesting both formulas. We concluded that CF patients have increasing difficulty maintaining their nutrition as their pulmonary disease progresses, in part because of a 17-20% increase in their BEE.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Hepatic bile salt sulfotransferases in the rat: sulfation of 3 beta-hydroxy-5-cholenoate during development.
Bile salt sulfotransferase (BSS) activity for the fetal bile acid, 3 beta-hydroxy-5-cholenoate, was first detected in the fetus at 18-19 days of gestation and was twofold greater than for glycolithocholate. The near-term (20-21 days of gestation) and newborn pup BSS activity was only 5-10% of that in maternal liver. The 3 beta-hydroxy-5-cholenoate sulfotransferase activity rose by the second day of life to levels observed in the mature male, and to activities greater than the mature female by the time of weaning at 3 weeks of age. Sex differences in 3 beta-hydroxy-5-cholenoate sulfotransferase activity developed during adolescence (28-35 days of age), resulting in fivefold greater activity in the mature female compared with the male. Two isoenzyme activities (BSS I and BSS II) were identified in both sexes during development by DEAE-Sephadex A-50 ion-exchange chromatography of liver cytosol. In the fetal and newborn liver, only one isoenzyme activity was distinctly identified for both monohydroxy bile acids, corresponding to BSS I in older rats. After the first week of life, both BSS I and BSS II exhibited activity like glycolithocholate, but only one peak of activity was identified for 3 beta-hydroxy-5-cholenoate, corresponding to BSS I. The 3 beta-hydroxy-5-cholenoate sulfotransferase activity in the mature male was only 20% of the mature female because of a decline in BSS I activity in the male during adolescence. BSS I and II were further purified by taurocholate-Sepharose 4B chromatography.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Membrane conductance patterns during fertilization are sperm dependent in two sea urchin species.
The influence of the egg and sperm on the conductance changes at fertilization in the sea urchin were investigated through cross-fertilization of two Hawaiian species, Tripneustes gratilla and Pseudoboletia indiana. The current-voltage (I-V) relation, measured in voltage-clamped eggs at intervals over the period 2-16 min following the rise to a positive membrane potential that signals sperm attachment, differs significantly in the two species. The magnitude of the conductance change depends on the species of the fertilizing sperm in both homologous and heterologous crosses. This supports the hypothesis that currents during this period arise from sperm membrane channels incorporated into the egg at sperm-egg fusion. Measurements of conductance during the first 90 sec, which includes the period of the major inward current correlated with cortical granule breakdown and elevation of the fertilization envelope, showed that the magnitude and timing of the maximum current also differed in the two species. This conductance change presumably involves an activation of egg membrane channels initiated by the sperm and would be expected to be characteristic of the egg species. However, in cross-fertilized eggs the magnitude and timing of the conductance change over this period also depends on the species of the sperm with little identifiable egg contribution, indicating that the fertilizing sperm can modulate the egg response to influence these events.
Animals↗
Effect of aging on hepatic biotransformation in female Fischer 344 rats: changes in sulfotransferase activities are consistent with known gender-related changes in pituitary growth hormone secretion in aging animals.
The effect of aging on hepatic drug conjugation in 5- to 6-, 12- to 13- and 22- to 23-month-old female Fischer 344 rats was examined. The overall disposition of acetaminophen including the formation and elimination kinetics of its sulfate and glucuronide metabolites were used as in vivo probes. The effects of aging on selected in vitro drug metabolizing enzyme activities and on the pattern of phenol and bile salt sulfotransferase isoenzymes were also determined. Aging decreased the total clearance of acetaminophen and the partial clearance of acetaminophen to acetaminophen sulfate by 36 and 47%, respectively. Increasing age also resulted in a reduced partial clearance of acetaminophen to the glucuronide- (24%) and to the glutathione-derived conjugates (29%). UDP glucuronosyltransferase activity toward 1-naphthol, morphine and testosterone was unaffected by advanced age, whereas there was a significant correlation between increased age and increased UDP glucuronosyltransferase activity toward estrone. Cytochrome P-450 concentration and glutathione-S-transferase activity toward 1-chloro-2,4-dinitrobenzene were unchanged by aging. Oxidative demethylase activity toward p-nitroanisole was decreased 18% and sulfotransferase activities toward p-nitrophenol, acetaminophen and glycolithocholate were decreased 27, 12 and 12%, respectively, in the 22- to 23-month-old rats, compared to the 5- to 6-month-old animals. In contrast to the age-related feminization in the pattern of sulfotransferase isoenzyme activities that occurs in male rats, there was no effect of aging on the pattern of phenol and bile salt sulfotransferase isoenzyme activities in female rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetaminophen↗
Glucose intolerance with low-, medium-, and high-carbohydrate formulas during nighttime enteral feedings in cystic fibrosis patients.
Ten young adult cystic fibrosis (CF) patients over 16 years of age (average 21.4 years) began nighttime enteral feedings as a method of nutritional rehabilitation to regain and maintain body weight. Patients received nighttime feedings of 1,000 kcal/M2 of a low- (Pulmocare), medium- (Ensure Plus), or high-carbohydrate (Vivonex) formula for at least 2 nights each with pancreatic enzyme therapy. Five of ten young adult CF patients developed nocturnal hyperglycemia (serum glucose greater than 300 mg/dl) and glucosuria (1-3% glucose) with varying degrees of polyuria during enteral feedings. No patient developed ketonuria despite serum glucoses at times greater than 600 mg %. There was no difference between the hyperglycemic and normoglycemic groups in median age, percent of ideal body weight, NIH score, Brasfield scores, pulmonary function tests, or family history of diabetes. All normoglycemic and four of five hyperglycemic patients had normal fasting blood sugars. The percent hemoglobin A1c was greater in the glucose intolerant group than the normoglycemic patients (11.2 +/- 0.8% vs. 6.8 +/- 1.1%, mean +/- SE, p less than 0.005). Twelve to 15 units of NPH insulin prior to initiation of feedings provided adequate therapy in most hyperglycemic patients. There was no apparent difference in the elevation of early morning serum glucoses with the low- medium- and high-carbohydrate formulas. We concluded that hyperglycemia requiring insulin therapy was common in young adult CF patients using nighttime enteral feedings. A hemoglobin A1c appeared to be a useful screening test before initiating such therapy.
Adult↗
Orthotopic liver transplantation resulting in amitriptyline toxicity in the recipient.
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Adult↗
Initial results of a program in liver transplantation.
St. Louis University established a liver transplant program in early 1988. The authors report on the program's first 10 months in operation, emphasizing the careful planning and cooperation the medical center must undertake to ensure the program's success.
Female↗
Perinatal cimetidine exposure has no apparent effect on hepatic drug oxidative or conjugative activity in adult male rat offspring.
UNLABELLED: Perinatal exposure of male rat pups to cimetidine has been reported to 'feminize' gonadal and sexual function and to reduce serum testosterone in adult male offspring. This study examined whether perinatal cimetidine exposure altered the androgen 'imprinting' of sex differences in mature male hepatic biotransformation capacities. During the perinatal period, dams were infused with cimetidine (18 mg/kg/day) through Alzet osmotic pumps placed subcutaneously beginning at 10 days of gestation. Pump function was confirmed by weekly high-performance liquid chromatographic analysis of maternal urine for unchanged cimetidine. Male pups were culled at birth with continued exposure to cimetidine in breast milk until weaning. At about 100 days of age, in vitro and in vivo drug oxidative and conjugative activities were measured in mature males. Early cimetidine exposure did not alter hepatic oxidative (cytochrome P-450 content or monooxygenase activity) or conjugative (UDP-glucuronosyltransferase activity towards testosterone, morphine, 1-naphthol, estrone, or sulfotransferase activity towards acetaminophen or glycolithocholate) capacities in mature males. Two sulfotransferase isoenzyme activities (acetaminophen sulfotransferase 2 and bile salt sulfotransferase I) previously shown to be regulated by gonadal hormones were also unchanged. Serum testosterone was unaffected by perinatal cimetidine exposure. Moreover, there were no effects of perinatal cimetidine exposure on in vivo pharmacokinetics or metabolic fate of acetaminophen. CONCLUSION: Perinatal exposure of male pups to doses of cimetidine similar to those used in humans did not appear to affect the imprinting of sex differences on in vitro hepatic drug metabolism or elimination kinetics of acetaminophen.
Acetaminophen↗
Cost savings and economic considerations using home intravenous antibiotic therapy for cystic fibrosis patients.
Our Cystic Fibrosis (CF) Center made an effort to utilize home intravenous antibiotic therapy (HIVAT) as an alternative to continued hospitalization during a 1-year study. After thorough individual clinical and financial evaluation, 27 of 41 CF patients admitted for treatment, including antibiotic therapy, were selected for HIVAT to complete a 14- to 21-day treatment course (mean 15.1 days). The 27 patients (6-28 years old, mean 16 years) incurred a total of $698,587 in hospital charges and physician fees during 96 admissions. The average charge for 974 inpatient days was $717/day ($7,280 per admission). After an average of 10.2 days of inpatient care, the 27 patients underwent 79 courses of HIVAT for an additional 8 days; 21 additional HIVAT courses in six of these patients were initiated on an outpatient basis between frequent readmissions. The 811 days of HIVAT resulted in $85,027 total charges by two home care companies. The charges per day of HIVAT by one company were almost twice that of the other. The average daily cost of HIVAT was $108/day. If the HIVAT patients had remained hospitalized to complete the course of intravenous antibiotic therapy, the projected inpatient costs would have been $589,271. Therefore, the 811 days of HIVAT over a 1-year period resulted in total estimated direct cost savings of $501,770. The average savings per course of HIVAT was $5,017, or $618/day.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗