Sample records for aminopyrine
-
Impairment of aminopyrine clearance in aspirin-damaged canine gastric mucosa
DOE Office of Scientific and Technical Information (OSTI.GOV)
Miller, T.A.; Henagan, J.M.; Loy, T.M.
Using an in vivo canine chambered stomach preparation, the clearance of (/sup 14/C)aminopyrine across mucosa when intravenously infused and the back-diffusion of this substance from gastric lumen to mucosa when topically applied to gastric epithelium were evaluated in aspirin-damaged gastric epithelium. In mucosa damaged by either 20 mM or 40 mM aspirin, the recovery of (/sup 14/C)aminopyrine, when topically mixed with acid (pH . 1.1) perfusate solution, was not significantly different from nondamaged control mucosa. In addition, the degree of ''trapping'' of this substance from back-diffusion was not different in damaged mucosa from that observed in nondamaged epithelium. In contrast,more » when (/sup 14/C)aminopyrine was intravenously infused, its clearance was significantly impaired in aspirin-damaged mucosa when compared with control studies, as evidenced by the increased ''trapping'' of this substance in injured epithelium. These findings indicate that movement of aminopyrine from plasma to gastric lumen is impaired in damaged epithelium, making the aminopyrine clearance technique an unreliable method to accurately measure absolute gastric blood flow in this experimental setting.« less
-
Merkel, C; Morabito, A; Sacerdoti, D; Bolognesi, M; Angeli, P; Gatta, A
1998-06-01
The determination of aminopyrine breath test on entry into the study was recently shown to improve the accuracy of prediction of death based on the Child-Pugh classification, but the possible usefulness of serial determinations of both parameters has not been assessed. In the present study, we aimed at evaluating whether serial determinations of aminopyrine breath test and Child-Pugh score improve prognostic accuracy in patients with cirrhosis, compared with determinations obtained only on admission. In 74 patients with liver cirrhosis aminopyrine breath test and Child-Pugh score were obtained upon entry into the study. Patients were followed with sequential aminopyrine breath tests and assessments of the Child-Pugh score every 4-6 months. A total number of 232 determinations were obtained. During follow-up 45 patients died, on average after 12 months of follow-up. Child-Pugh score improved in the beginning of follow-up, and then remained fairly constant; aminopyrine breath test showed no improvement in the beginning of follow-up, but rather a slowly progressive decline. In patients who died, both the Child-Pugh score and the metabolism of aminopyrine were significantly more impaired in the last year preceding death (p < 0.05). Applying Cox's regression model with time-dependent covariates, Child-Pugh score and aminopyrine breath test were independent significant predictors of survival. The model with time-dependent covariates explained the observed survival much better than the model with time-fixed covariates (chi-sq. explained by regression = 31.45 vs 11.97; d.f. = 2; p = 0.0000001 vs 0.003). These data suggest that serial determinations of Child-Pugh score and aminopyrine breath test can be used to efficiently update prognosis of cirrhosis.
-
Kodaira, Chise; Uchida, Shinya; Yamade, Mihoko; Nishino, Masafumi; Ikuma, Mutsuhiro; Namiki, Noriyuki; Sugimoto, Mitsushige; Watanabe, Hiroshi; Hishida, Akira; Furuta, Takahisa
2012-03-01
Aminopyrine is metabolized by cytochrome P450 (CYP) in the liver. The investigators evaluated influences of different PPIs on CYP activity as assessed by the [(13)C]-aminopyrine breath test ([(13)C]-ABT). Subjects were 15 healthy volunteers with different CYP2C19 status (5 rapid metabolizers [RMs], 5 intermediate metabolizers [IMs], and 5 poor metabolizers [PMs]). Breath samples were collected before and every 15 to 30 minutes for 3 hours after oral ingestion of [(13)C]-aminopyrine 100 mg on day 8 of each of the following regimens: control; omeprazole 20 mg and 80 mg, lansoprazole 30 mg, and rabeprazole 20 mg. Changes in carbon isotope ratios in carbon dioxide ((13)CO(2)/(12)CO(2)) in breath samples were measured by infrared spectrometry and expressed as delta-over-baseline (DOB) ratios (‰). Mean areas under the curve of DOB from 0 to 3 h (AUC(0-3h) of DOB) were significantly decreased by omeprazole 20 mg and lansoprazole 30 mg but not by rabeprazole 20 mg. Conversely, higher PPI dose (ie, omeprazole 80 mg) seemed to further decrease AUC(0-3h) of DOB in RMs but increased it in PMs. Omeprazole and lansoprazole at the standard doses inhibit CYP activity but rabeprazole does not, whereas high-dose omeprazole seems to induce CYPs.
-
Wutzke, Klaus D; Wigger, Marianne
2009-09-01
The aim of this study was to investigate the hepatic microsomal and cytosolic functions by using the 13CO2 breath test in healthy subjects either before or after consumption of red wine. Twelve adults received [13C2]aminopyrine and L-[1-13C]phenylalanine together with a standardised dinner. Expired air samples were taken over 6 h. After a wash-out period, the subjects consumed 0.4 ml ethanol per kg per day together with dinner over a 7.5-day period on average. Thereafter, 13C-tracer administration was repeated under identical conditions. The 13CO2 enrichments were measured by isotope ratio mass spectrometry. The mean cumulative percentage 13C-dose recovery after administration of [13C2]aminopyrine and L-[1-13C]phenylalanine either without or with red wine consumption amounted to 17.0+/-4.4 vs. 14.7+/-3.1% (p=0.170) and 14.0+/-2.8 vs. 11.5+/-3.9% (p=0.084), respectively. Moderate alcohol consumption does not induce significant short-term changes of the microsomal and the cytosolic function of the human liver in healthy subjects.
-
Cai, Mei-Quan; Feng, Li; Zhang, Li-Qiu
2017-03-01
Aminopyrine (AMP) has been frequently detected in the aquatic environment. In this study, the transformation mechanism of AMP by free available chlorine (FAC) oxidation was investigated. The results showed that FAC reacted with AMP rapidly, and a 74% elimination was achieved for 1.30 μM AMP after 2 min at 14.08 μM FAC dose. AMP chlorination was strongly pH-dependent, and its reaction included second- and third-order kinetic processes. Three active FAC species, including chlorine monoxide (Cl 2 O), molecular chlorine (Cl 2 ), and hypochlorous acid (HOCl), were observed to contribute to AMP degradation. The intrinsic rate constants of each FAC species with neutral (AMP 0 ) and cation (AMP + ) species were obtained by kinetic fitting. Cl 2 O exhibited the highest reactivity with AMP 0 (k AMP0, Cl2O = (4.33 ± 1.4) × 10 9 M -1 s -1 ). In addition, Cl 2 showed high reactivity (10 6 -10 7 M -1 s -1 ) in the presence of chloride, compared with HOCl (k AMP+, HOCl = (5.73 ± 0.23) × 10 2 M -1 s -1 , k AMP0, HOCl = (9.68 ± 0.96) × 10 2 M -1 s -1 ). At pH 6.15 and 14.08 μM FAC dose without chloride addition, the contribution of Cl 2 O reached to the maximum (33.3%), but in the whole pH range, HOCl was the main contributor (>66.6%) for AMP degradation. The significance of Cl 2 was noticeable in water containing chloride. Moreover, 11 transformation products were identified, and the main transformation pathways included pyrazole ring breakage, hydroxylation, dehydrogenation, and halogenation. Copyright © 2016 Elsevier Ltd. All rights reserved.
-
Oshino, N; Chance, B
1977-01-01
The enhanced reduction of t-butyl hydroperoxide by glutathione peroxidase is accompanied by a decrease in the cellular concentration of both glutathione and NADPH in isolated liver cells, resulting in the release of GSSG (oxidized glutathione) from the perfused rat liver. This phenomenon, first reported by H. Sies, C. Gerstenecker, H. Menzel & L. Flohé (1972) (FEBS Lett. 27, 171-175), can be observed under a variety of conditions, not only with the acceleration of the glutathione peroxidase reaction by organic peroxides, but also during the oxidation of glycollate and benzylamine, during demethylation of aminopyrine in the liver of the phenobarbital-pretreated rat and during oxidation of uric acid in the liver of the starved rat pretreated with 3-amino-1,2,4-triazole. The rate of release of GSSG is altered markedly by changes in the metabolic conditions which affect the rate of hepatic NADPH generation. Thus, regardless of whether achieved by enhanced oxidation of glutathione by glutathione peroxidase or by oxidation of NADPH through other metabolic pathways, an increase in the cellular concentration of GSSG appears to facilitate its release. It has been found that, in addition to the hexose monophosphate shunt, the mitochondrial NADH-NADP+ transhydrogenase reaction plays an important role in supplying reducing equivalents to the glutathione peroxidase reaction and in maintaining the cellular oxidation-reduction state of the nicotinamide nucleotides. Spectrophotometric analysis of the steady-state concentration of the catalase-H2O2 intermediate with simultaneous measurement of the rate of release of GSSG leads to the conclusion that intracellular compartmentation of catalase in the peroxisomes and glutathione peroxidase in the cytosol and mitochondria distinguishes the reactivities of these enzymes one from the other, and facilitates their effective cooperation in hydroperoxide metabolism in the liver. PMID:17386
-
Ibii, N; Horiuchi, M; Yamamoto, K
1984-08-01
Interactions between 450191-S and other representative drugs which might be clinically used with 450191-S were behaviorally investigated in mice, and compared with the cases of nitrazepam, estazolam and triazolam. The potencies of 450191-S and nitrazepam in preventing pentetrazol convulsions were markedly decreased by aminopyrine, whereas that of estazolam was remarkably increased by phenytoin. Administration of nitrazepam with other drugs, except aminopyrine, or of estazolam together with haloperidol exhibited an anticonvulsive pattern different from the case of dosing with either drug alone. Only the effect of triazolam was not influenced by any drugs used. The potency of haloperidol against apomorphine-induced climbing behavior was significantly reduced by nitrazepam, and the pattern of the haloperidol effect was changed by treatment together with 450191-S or estazolam. However, triazolam had no influence on the effect of haloperidol. The antagonistic activity of imipramine to reserpine-induced hypothermia was slightly decreased by 450191-S, estazolam and triazolam, but little affected by nitrazepam. In the protection from maximal electroshock convulsions (MEC), the potency of phenytoin was significantly decreased by 450191-S and triazolam. Moreover, the anti-MES pattern of phenytoin was altered by nitrazepam. Estazolam exerted no significant influence on the effect of phenytoin. Analgesic activities of morphine and/or aminopyrine were potentiated by pretreatment with sleep-inducers, but not 450191-S. Thus, judging from the potency and stability of the anti-pentetrazol effect, 450191-S seems to be inferior to triazolam, but superior to nitrazepam and estazolam. Also, 450191-S may be differentiated from other sleep-inducers by the fact that only 450191-S did not potentiate the analgesic activities of morphine and aminopyrine.
-
[Immunomodulators with an 8-azasteroid structure as inducers of liver cytochrome P-450].
Kuz'mitskiĭ, B B; Dad'kov, I G; Mashkovich, A E; Stoma, O V; Slepneva, L M
1990-01-01
Two structural analogues of D-homo-8-azasteroids, both an immunostimulant and an immunodepressant, are inductors of the liver cytochrome P-450 in animals. This capability was shown by means of both a decrease of the hexenal sleep duration in the pharmacological test and an increase of the quantity of cytochrome P-450 and the rate of N-demethylation of aminopyrine in the biochemical assays.
-
Gas-chromatographic determination of camylofine dihydrochloride in tablets and suppositories.
Crombez, E; van den Bossche, W; De Moerloose, P
1976-02-04
A gas-chromatographic method for the quantitative determination of camylofine dihydrochloride, a spasmolytic agent, is described. The analysis is made on a porous polymer packing material, by determining the 3-methyl-1-butanol formed on alkaline hydrolysis of the drug. The method has been applied to the quantitative determination of the drug in two galenical forms, namely tablets and suppositories, in the presence of papaverine hydrochloride, codeine phosphate, novalgin and aminopyrine.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Pfeiffer, A.; Rochlitz, H.; Herz, A.
The muscarinic receptor system involved in hydrogen production by enriched rat gastric parietal cells was investigated. Muscarinic receptor density determined by (N-methyl-{sup 3}H)scopolamine binding was 8,100/cell. The receptor appeared to be of the M{sub 2} muscarinic receptor subtype, since it had a low affinity (K{sub d} 189 nM) for the M{sub 1} receptor antagonist pirenzepine compared with atropine. Receptor activation by carbachol rapidly augmented levels of polyphosphoinositides, indicating an activation of phospholipase C. The dose-response relations for the increase in inositol phosphates closely paralleled the binding of carbachol to muscarinic receptors. The inositol phosphate response was antagonized by pirenzepine withmore » a K{sub i} of 177 nM. the stimulation of inositol phosphate levels by carbachol correlated well with the stimulation of ({sup 14}C)aminopyrine uptake, determine as an index of acid secretion. The muscarinic agonists oxotremorine, pilocarpine, and bethanechol elicited partial increases in inositol phosphates at maximal drug concentrations, and these partial increases correlated with their ability to stimulate ({sup 14}C)aminopyrine uptake. These data indicate that inositolpolyphosphates may be a second messenger of M{sub 2} receptors stimulating acid secretion.« less
-
The oxidation of drugs by fishes
Buhler, Donald R.; Rasmusson, Mary E.
1968-01-01
1. Fish liver microsomal systems have been found to catalyze the hydroxylation of aniline and acetanilide, the N-demethylation of aminopyrine and the O-dealkylation of phenacetin.2. These systems are similar to the corresponding mammalian enzymes and they may be considered to be mixed function oxidase since they require NADPH and oxygen. An absolute requirement for oxygen, however, was difficult to demonstrate for the hepatic phenacetin cleavage system from fish.3. Microsomal drug metabolizing systems from fish have temperature optima which are considerably lower than those of corresponding mammalian systems
-
1982-12-23
assay Blanks and reaction mixtures were the same as in aminopy- rine demethylase assay except 0.5 ml of 153.64 mM aniline in 0.1 M phosphate buffer...replaced the 0.5 ml aminopyrine. (Final concentration of aniline in the reaction mixture was 25.61 mM). At the end of the 20 minute incubation period, the...with PB, 3MC, or PCB. Aniline hydroxylase activity did not change folowing PB treatment , however it did in- crease when 3MC or PCB were used as the
-
Favier, Maxime; Dewil, Raf; Van Eyck, Kwinten; Van Schepdael, Ann; Cabooter, Deirdre
2015-10-01
Phenazone-type pharmaceuticals, such as aminopyrine, metamizole, phenazone and propyphenazone, are widely used analgesics that have been detected in wastewater treatment plant effluents in μg L(-1) concentrations. Acetamido antipyrine (AAA) and formyl aminoantipyrine (FAA) - the main metabolites of aminopyrine and metamizole - have also been detected in sub μg L(-1) concentrations in environmental water bodies and in resources used to produce drinking water, suggesting their highly persistent character. In this study phenazone, propyphenazone, AAA and FAA were treated with ozone under laboratory conditions and 17 degradation products were identified by an elucidation approach based on high-resolution mass spectrometry (LTQ Orbitrap). Typical oxidation of carbon-carbon double bonds by ozone was observed among other mechanisms of ring opening. It was demonstrated that reactivity of these compounds with ozone is high (rate constants kO3 ranging from 6.5×10(4) to 2.4×10(6) M(-1) s(-1)). The toxicity of the degradation products from ozonation was estimated by quantitative structure-activity relationships (QSAR). It was shown that, when the carbon-carbon double bond is partially oxidized to an epoxy, the toxicity towards fish and daphnids is higher than that of the parent compound. By further oxidizing the molecules, a common degradation product - 1-acetyl-1-methyl-2-phenylhydrazide (AMPH) - was also found to be more toxic than its parent compounds, which is of concern since this compound has previously been reported in environmental waters. Copyright © 2015 Elsevier Ltd. All rights reserved.
-
The effects of estrus cycle on drug metabolism in the rat.
Brandstetter, Y; Kaplanski, J; Leibson, V; Ben-Zvi, Z
1986-01-01
The effect of the female rat estral cycle on microsomal drug metabolism in-vivo and in-vitro has been studied. Two microsomal enzymes, aminopyrine-N-demethylase and aniline hydroxylase showed a greater specific activity (p less than 0.01) in the diestrus phase of the estral cycle while the oxidative enzyme aryl hydrocarbon hydroxylase and the conjugative enzyme, glucuronyl transferase, were not affected. In vivo studies which included theophylline and antipyrine metabolism, and hexobarbital sleeping times showed no difference between the different phases of the estral cycle. Conflicting evidence about the effect of steroid sex hormones on hepatic drug metabolism is discussed.
-
NASA Technical Reports Server (NTRS)
Zhang, S. Y.; Wang, G. F.; Wu, Y. T.; Baldwin, K. M. (Principal Investigator)
1993-01-01
On a partition chromatographic column in which the support is Kieselguhr and the stationary phase is sulfuric acid solution (2 mol/L), three components of compound theophylline tablet were simultaneously eluted by chloroform and three other components were simultaneously eluted by ammonia-saturated chloroform. The two mixtures were determined by computer-aided convolution curve method separately. The corresponding average recovery and relative standard deviation of the six components were as follows: 101.6, 1.46% for caffeine; 99.7, 0.10% for phenacetin; 100.9, 1.31% for phenobarbitone; 100.2, 0.81% for theophylline; 99.9, 0.81% for theobromine and 100.8, 0.48% for aminopyrine.
-
Biodegradation of kerosene by Aspergillus ochraceus NCIM-1146.
Saratale, Ganesh; Kalme, Satish; Bhosale, Sanjyot; Govindwar, Sanjay
2007-10-01
The filamentous fungus Aspergillus ochraceus NCIM-1146 was found to degrade kerosene, when previously grown mycelium (96 h) was incubated in the broth containing kerosene. Higher levels of NADPH-DCIP reductase, aminopyrine N-demethylase and kerosene biodegradation activities were found to be present after the growth in potato dextrose broth for 96 h, when compared with the activities at different time intervals during the growth phase. NADPH was the preferred cofactor for enzyme activity, which was inhibited by CO, indicating cytochrome P450 mediated reactions. A significant increase in all the enzyme activities was observed when mycelium incubated for 18 h in mineral salts medium, containing cholesterol, camphor, naphthalene, 1,2-dimethoxybenzene, phenobarbital, n-hexane, kerosene or saffola oil as inducers. Acetaldehyde produced by alcohol dehydrogenase could be used as an indicator for the kerosene biodegradation.
-
Hepatic effects of orally administered styrene in rats.
Srivastava, S P; Das, M; Mushtaq, M; Chandra, S V; Seth, P K
1982-08-01
Adult male rats receiving styrene by gavage (200 or 400 mg kg-1, 6 days a week) for 100 days exhibited a significant dose-dependent increase in hepatic benzo[a]pyrene hydroxylase and aminopyrine-N-demethylase, a decrease in glutathione-S-transferase and no change in glucose-6-phosphatase. A decrease in the activity of mitochondrial succinic dehydrogenase and beta-glucuronidase was also observed. Activity of acid phosphatase was decreased only at the higher dose level. Levels of serum glutamic oxaloacetic transaminase and glutamic pyruvic transaminase were elevated only at the higher dose level. The absolute and relative weights of the liver of control and treated animals showed no significant difference. Histopathological studies of the liver tissue revealed tiny areas of focal necrosis, consisting of few degenerated hepatocytes and inflammatory cells at the higher dose level only.
-
Cellular site of gastric acid secretion.
DiBona, D R; Ito, S; Berglindh, T; Sachs, G
1979-01-01
Isolated gastric glands of the rabbit were examined both with differential interference-contrast microscopy and with electron microscopy to describe the morphologic correlates of acid secretion. Stimulation of the glands with histamine resulted in the development of intracellular spaces within the parietal cells. A similar transformation was produced by addition of 1 mM aminopyrine, whether the weak base was added in the presence of normal-K+ (5.4 mM) or high-K+ (108 mM) solutions. The intracellular space was compatible with the expanded canaliculus described in stimulated parietal cells. Confirmation that the space produced by histamine is the site of acid secretion was gained by combining fluorescence and interference-contrast methods in the presence of the dye acridine orange, which displays a pH-dependent metachromasia in its emission spectrum. Human gastrin I resulted in an observable discharge of peptic granules. Images PMID:42918
-
Induction of microsomal drug metabolism in man and in the rat by exposure to petroleum.
Harman, A W; Frewin, D B; Priestly, B G
1981-01-01
To determine the effect of petroleum exposure on the activity of hepatic mixed function oxidase enzymes, salivary elimination kinetics of antipyrine were determined in 19 petrol station attendants and compared with 19 controls. Antipyrine half life in petrol station attendants was shorter than in controls. Microsomal preparations (10 000 x g supernatants) were prepared from six male Porton rats exposed to petrol vapour (5 ppm at an air flow rate of 41/min for eight hours a day for three weeks) and six control rats maintained under the same conditions without exposure to petrol vapour. The rates of oxidative metabolism of antipyrine, aminopyrine, ethylmorphine, aniline, and benzo(a)pyrene were all increased by more than 45% in the petrol-exposed rats. The results indicate that petrol vapour is a moderately potent inducer of mixed function oxidase activity in rats, and that occupational exposure to petroleum may result in enhanced microsomal drug metabolism. PMID:7470408
-
Sewing, K F; Harms, P; Schulz, G; Hannemann, H
1983-01-01
The inhibitory effect of the three benzimidazole derivatives timoprazole, picoprazole, and omeprazole on histamine and dbcAMP stimulated 14C-aminopyrine accumulation (= H+ secretion) has been studied in isolated and enriched guinea-pig parietal cells. All compounds tested inhibited H+ secretion in a concentration dependent manner with IC50 values of 8.5 +/- 1.9 mumol/l for timoprazole, 3.9 +/- 0.7 mumol/l for picoprazole, and 0.13 +/- 0.03 mumol/l for omeprazole. The IC50 of timoprazole, when dbcAMP was used as a stimulus, did not differ significantly from that of histamine stimulation. The type of inhibition was of a non-competitive nature. The full acid response to histamine after temporary exposure of the cells to the benzimidazoles could be restored by washing the cells twice; this suggests that the inhibition is reversible. The data - among others - indicate that the properties of the benzimidazoles described here would allow these compounds to be used as effective antisecretagogues. PMID:6303916
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Chiba, T.; Fisher, S.K.; Park, J.
The potential role of inositol phospholipid turnover in mediating acid secretion was examined in a preparation enriched for isolated canine gastric parietal cells. The stimulatory effects of carbamoylcholine (carbachol) and gastrin on parietal cell uptake of ({sup 14}C)aminopyrine were linked to dose- and time-dependent selective reduction in cellular phosphatidylinositol content, although the specific fatty acid composition of the phosphoinositides was not altered. Analysis of ({sup 3}H)inositol phosphates accumulated in cells prelabeled with ({sup 3}H)inositol revealed an increase in labeled inositol trisphosphate by 5 min of incubation with either carbachol or gastrin. Furthermore, after preincubation of parietal cells in medium containingmore » ({sup 32}P)orthophosphate, the two secretagogues elicited a time-dependent decrease in {sup 32}P labeling of phosphatidylinositol 4,5-bisphosphate and concomitant increase in labeling of phosphatidic acid. These data demonstrate that the acid secretagogue actions of carbachol and gastrin are correlated with turnover of cellular inositol phospholipids in a preparation consisting predominantly of parietal cells.« less
-
Halofuginone can worsen liver fibrosis in bile duct obstructed rats.
Van de Casteele, Marc; Roskams, Tania; Van der Elst, Ingrid; van Pelt, Jos F; Fevery, Johan; Nevens, Frederik
2004-10-01
Halofuginone (HF) is an antifibrotic agent in rat models of liver fibrosis caused by repetitive intoxications. A beneficial effect of HF on a biliary type of liver fibrosis has not been proven yet. Bile duct-obstructed rats were given HF from the moment of obstruction onwards and compared with no treatment. After 3 weeks, respectively, 6 weeks, aminopyrine breath test (ABT) and haemodynamic measurements including of portal pressure were carried out. Liver pieces were taken for Sirius red quantitative scoring, as well as for semiquantitative determinations of collagen type I and III RNA levels. ABT was significantly worse in HF-treated rats as compared with no treatment (P=0.02). Haemodynamic data and collagen type I and III determinations were not significantly different between groups. Biliary fibrosis scores were significantly higher in HF-treated rats as compared with no treatment (P=0.03). More Sirius red staining was associated with more proliferation of bile ductules. HF may worsen biliary fibrosis. This contrasts sharply with antifibrotic effects in other models of liver fibrosis. Distinctive cellular mechanisms in biliary fibrosis may explain this discrepancy. One should be cautious for chronic application of HF in man with cholestasis.
-
STUDIES ON THE PATHOGENESIS OF FEVER
Petersdorf, Robert G.; Bennett, Ivan L.
1957-01-01
Intravenous administration of bacterial endotoxins in dogs is followed within 2 hours by the appearance of a fever-producing substance in the blood. This endogenous pyrogen differs from the endotoxins originally administered by its ability to produce fever in tolerant recipients and failure to promote tolerance after repeated daily injections. Endogenous serum pyrogen is destroyed by heating at 90°C. for 30 minutes, and is also inactivated to some degree by incubation at 37°C. for 24 hours. Suppression of fever by aminopyrine does not affect appearance of the endogenous factor. Animals made febrile with dinitrophenol, kaolin, or lysergic acid do not elaborate a fever-promoting substance in the blood. Sterile abscesses, accompanied by elevations in body temperature of the host, are unassociated with detectable amounts of secondary pyrogen in the serum. The absence of endogenous pyrogen in the blood of febrile dogs made leukopenic with nitrogen mustard favors the idea that polymorphonuclear leukocytes injured by endotoxins release the endogenous factor. On the other hand, the finding that the granulocytopenic animals are febrile when no circulating endogenous pyrogen is present, casts doubt upon the essential role of this substance in endotoxin fever. PMID:13449238
-
Toxicity of trichlorotoluene isomers: a 28-day feeding study in the rat.
Chu, I; Shen, S Y; Villeneuve, D C; Secours, V E; Valli, V E
1984-03-01
Groups of 10 male and 10 female rats were fed alpha,alpha,alpha-, alpha,2,6- or 2,3,6- trichlorotoluene (TCT) in their diet at 0, 0.5, 5.0, 50 or 500 ppm for 28 days. Growth rate and food consumption were not affected by treatment. No deaths occurred. Significant increases in liver weights were observed in male rats fed 5.0 and 500 ppm 2,3,6-TCT. Mild serum biochemical changes occurred in male rats. These included increased SDH activities in the groups fed 5.0 and 50 ppm alpha, alpha, alpha-TCT, and 5.0 ppm 2,3,6-TCT. Alpha, alpha, alpha-TCT at 500 ppm caused elevated LDH activities in male rats. Hepatic microsomal aminopyrine N-demethylase activities were increased in male rats fed 500 ppm alpha,2,6-TCT. Hematological parameters were not affected by treatment. Mild histological changes were seen in the liver, kidney and thyroid of treated rats. Data presented here suggest that alpha, alpha, alpha-, alpha,2,6- and 2,3,6-TCT possess a low order of oral toxicity in the rat.
-
Functional restoration of cirrhotic liver after partial hepatectomy in the rat.
Hashimoto, Masaji; Watanabe, Goro
2005-01-01
Although cirrhosis is the terminal stage of various liver diseases, thanks to recent advances one might eliminate some causes of liver damage. Liver has a potent regeneration capacity. It is important to evaluate the regenerating cirrhotic liver after partial hepatectomy, morphologically and functionally, in the long term. We evaluated the functional capacity of the rat liver rendered cirrhotic by orally administered thioacetamide, and examined the correlation between morphological and functional restoration after 2/3 hepatectomy in comparison with hepatectomized normal rats and sham-operated cirrhotic rats. Morphological restoration was evaluated by remnant liver weight, proliferating cell nuclear antigen labeling index, and fibrosis ratio. Functional restoration was evaluated by the indocyanine green disappearance rate and aminopyrine clearance. Cirrhotic rats were functionally deteriorated in comparison with the normal rats. Morphological restoration in cirrhotic rats was delayed in comparison with normal rats. Functional restoration after 2/3 hepatectomy was advanced in comparison with morphological restoration. In comparison with sham-operated cirrhotic rats, functional restoration of the cirrhotic liver was accelerated by partial hepatectomy. In cirrhotic rats, functional restoration of the liver after 2/3 hepatectomy was advanced in comparison with morphological restoration. Partial hepatectomy seemed to promote functional restoration of the cirrhotic liver.
-
Neef, Markus; Ledermann, Monika; Saegesser, Hans; Schneider, Vreni; Reichen, Juerg
2006-12-01
Mammalian target of rapamycin (mTOR) signalling is central in the activation of hepatic stellate cells (HSCs), the key source of extracellular matrix (ECM) in fibrotic liver. We tested the therapeutic potential of the mTOR inhibitor rapamycin in advanced cirrhosis. Cirrhosis was induced by bile duct-ligation (BDL) or thioacetamide injections (TAA). Rats received oral rapamycin (0.5 mg/kg/day) for either 14 or 28 days. Untreated BDL and TAA-rats served as controls. Liver function was quantified by aminopyrine breath test. ECM and ECM-producing cells were quantified by morphometry. MMP-2 activity was measured by zymography. mRNA expression of procollagen-alpha1, transforming growth factor-beta1 (TGF-beta1) and beta2 was quantified by RT-PCR. Fourteen days of rapamycin improved liver function. Accumulation of ECM was decreased together with numbers of activated HSCs and MMP-2 activity in both animal models. TGF-beta1 mRNA was downregulated in TAA, TGF-beta2 mRNA was downregulated in BDL. 28 days of rapamycin treatment entailed a survival advantage of long-term treated BDL-rats. Low-dose rapamycin treatment is effectively antifibrotic and attenuates disease progression in advanced fibrosis. Our results warrant the clinical evaluation of rapamycin as an antifibrotic drug.
-
Gorowska-Kowolik, Katarzyna; Chobot, Agata; Kwiecien, Jaroslaw
2017-01-01
Assessment of the liver function, and the need of constant monitoring of the organ's capacity, concerns not only patients with primary liver diseases, but also those at risk of hepatopathies secondary to other chronic diseases. Most commonly, the diagnostics is based on measurements of static biochemical parameters, which allow us to draw conclusions only indirectly about the function and the degree of damage of the organ. On the other hand, liver biopsy is an invasive procedure and therefore it is associated with a considerable risk of complications. Dynamic tests enable us to assess quantitatively the organ's functional reserve by analyzing the kinetics of the metabolization of the substrate by the liver. In practice applied are breath tests using substances such as aminopyrine, caffeine, methacetin, erythromycin (for assessment of the microsomal function); phenylalanine, galactose (for assessment of the cytosolic function); methionine, octanoate, ketoisocaproic acid (for assessment of the mitochondrial function). The test with 13 C methacetin belongs to the best described and most widely applied methods in noninvasive liver function assessment. Due to the rising availability of this method, knowledge concerning its limitations and controversies regarding the methodology, as well as its usefulness in chosen groups of patients, seems to be vital.
-
Huang, Ya-Jun; Cheng, Pi; Zhang, Zhuo-Yi; Tian, Shi-Jie; Sun, Zhi-Liang; Zeng, Jian-Guo; Liu, Zhao-Ying
2018-01-11
In this study, the biotransformation in the plasma, urine and feces of rats following oral administration of protopine (PRO) and allocryptopine (ALL)were explored using HPLC-QqTOF MS. An HPLC-MS/MS method for the determination of tissues was developed and applied to the tissue distribution study in rats following intragastric administration of Plume Poppy Total Alkaloid for 3 weeks. A total of ten PRO metabolites and ten ALL metabolites were characterized in rats in vivo. Among these metabolites, six PRO metabolites and five ALL metabolites were reported for the first time. The predicated metabolic pathways including ring cleavage, demethylation following ring cleavage, and glucuronidation were proposed. The low-concentration residue of PRO and ALL in various tissues was detected at 24 h and 48 h after dosing, which indicated that both compounds could be widely distributed in tissues and exist as low levels of residue. The activities of erythromycin N-demethylase, aminopyrine N-demethylase and NAD (P)H quinone oxidoreductase in female rats can be induced post-dose, but these activities were inhibited in male rats. The proposed biotransformation and residues of PRO and ALL and their effects on enzymes may provide a basis for clarifying the metabolism and interpreting pharmacokinetics.
-
[Effect of bemethyl on cytochrome P-450-dependent monoxygenases in the human liver and lymphocytes].
Sorokina, E A; Sibiriak, S V; Sergeeva, S A
2002-01-01
Effects of the actoprotector bemithyl (50 mg/kg, p.o.) upon a single or five-fold administration on the cytochrome P-450 and b5 content and the isoform-specific and nonspecific monooxygenase activity [aminopyrine-N-demethylase, aniline-p-hydroxylase, 4-nitroanisole-o-demethylase,2,5-diphenyloxazole-p-hydroxylase, 7-ethoxyresorufin-o-deethylase (EROD), benzyloxyresorufin-o-debenzylase (BROD)] in rat liver were evaluated. In addition, the influence of bemithyl (0.(1)-100 microM) on the development of EROD and BROD activity was studied on the mitogen-stimulated human lymphocytes in vitro. Administered in rats, bemithyl exhibited the properties of a cytochrome P-450 inductor of the mixed type, which was manifested by an increase in the total cytochrome P-450 content in liver microsomes and in the monooxygenase activity related to both Ah-receptor-dependent and -independent isoforms (except for the aniline-p-hydroxylase activity). The induction of the monooxygenase activity realized by Ah-receptor-dependent isoforms (4-nitroanisole-o-demethylase, 2,5-diphenyloxazole-p-hydroxylase, and EROD activity) was more pronounced, reaching maximum upon a single drug administration. Acting upon the human lymphocytes in vitro, high concentrations of bemithyl increased expression of the EROD activity, while low drug concentrations stimulated the BROD activity.
-
Dong, Miao; Zhu, Lusheng; Shao, Bo; Zhu, Shaoyuan; Wang, Jun; Xie, Hui; Wang, Jinhua; Wang, Fenghua
2013-06-01
Endosulfan, an organochlorine pesticide, has been used worldwide in the past decades. The present study was performed to investigate the effect of endosulfan on liver microsomal cytochrome P450 (CYP) enzymes and glutathione S-transferases (GST) in zebrafish. Male and female zebrafish were separated and exposed to a control and four concentrations of endosulfan (0.01, 0.1, 1, and 10μgL(-1)) and were sampled on days 7, 14, 21, and 28. After exposure to endosulfan, the content of CYP increased and later gradually fell back to control level in most sampling time intervals. A similar tendency was also found in the activities of NADPH-P450 reductase (NCR), aminopyrine N-demethylase (APND) and erythromycin N-demethylase (ERND). GST activities were generally higher in treatment groups than control groups. Regarding sex-based differences, the induction degree of the activity of NCR was generally higher in males than females. Similar differences were also found on the 28th day in the activities of APND and ERND, as well as GST activity on the 7th day. Overall, the present results demonstrate the toxicity at low doses of endosulfan and indicated marked induction of CYP and GST enzymes in zebrafish liver. Copyright © 2012 Elsevier Inc. All rights reserved.
-
Prognostic Value of Metabolic Liver Function Tests: a Study on 711 Cirrhotic Patients.
Lebossé, Fanny; Guillaud, Olivier; Forestier, Julien; Ecochard, Marie; Boillot, Olivier; Roman, Sabine; Mion, François; Dumortier, Jérôme
2016-09-01
The prognosis of cirrhotic patients is usually assessed by Child-Pugh and MELD scores. Metabolic liver function tests such as aminopyrine breath test (ABT) and indocyanine green clearance (IGC) have been shown to reveal hepatocellular dysfunction. The aim of this retrospective study was to compare the prognostic value of the MELD score, Child-Pugh score, ABT and IGC in a large cohort of cirrhotic patients. Between January 1996 and June 2008, 711 cirrhotic patients were included and the primary endpoint was survival without LT. The ROC curves with c-statistics, correlation coefficient and survival were calculated. Metabolic function tests and scores were strongly correlated. At the time of evaluation, 111 patients had died and 520 had received a transplant. Prognostic ability (estimated by the AUROC curve) to predict survival without LT at 6 months was 0.662, 0.691, 0.738 and 0.715 for ABT, IGC, Child-Pugh score and MELD score, respectively. Similarly, at 1 year, AUROC was 0.738 for Child-Pugh score, 0.716 for MELD score, 0.693 for IGC clearance and 0.651 for ABT. Our results strongly confirm that IGC and ABT have a high prognostic value in cirrhotic patients, similar to Child-Pugh and MELD scores. They could be developed to routinely evaluate the prognosis of patients in addition to clinical and biochemical data.
-
Alteration in metabolism and toxicity of acetaminophen upon repeated administration in rats.
Kim, Sun J; Lee, Min Y; Kwon, Do Y; Kim, Sung Y; Kim, Young C
2009-10-01
Our previous studies showed that administration of a subtoxic dose of acetaminophen (APAP) to female rats increased generation of carbon monoxide from dichloromethane, a metabolic reaction catalyzed mainly by cytochrome P450 (CYP) 2E1. In this study we examined the changes in metabolism and toxicity of APAP upon repeated administration. An intraperitoneal dose of APAP (500 mg/kg) alone did not increase aspartate aminotransferase, alanine aminotransferase, or sorbitol dehydrogenase activity in serum, but was significantly hepatotoxic when the rats had been pretreated with an identical dose of APAP 18 h earlier. The concentrations and disappearance of APAP and its metabolites in plasma were monitored for 8 h after the treatment. APAP pretreatment reduced the elevation of APAP-sulfate, but increased APAP-cysteine concentrations in plasma. APAP or APAP-glucuronide concentrations were not altered. Administration of a single dose of APAP 18 h before sacrifice increased microsomal CYP activities measured with p-nitrophenol, p-nitroanisole, and aminopyrine as probes. Expression of CYP2E1, CYP3A, and CYP1A proteins in the liver was also elevated significantly. The results suggest that administration of APAP at a subtoxic dose may result in an induction of hepatic CYP enzymes, thereby altering metabolism and toxicological consequences of various chemical substances that are substrates for the same enzyme system.
-
Liu, Jingjing; Li, Qing; Yin, Yidi; Liu, Ran; Xu, Huarong; Bi, Kaishun
2014-01-01
A fast, sensitive, and efficient ultra-fast LC-ESI-MS/MS method was developed for the simultaneous quantitation of six highly toxic Aconitum alkaloids, that is, aconitine, mesaconitine, hypaconitine, benzoylaconine, benzoylmesaconine, and benzoylhypaconine, in rat plasma after oral administration of crude ethanol extracts from Aconiti kusnezoffii radix by ultrasonic extraction, reflux extraction for 1 h, and reflux extraction for 3 h, respectively. The separation of six Aconitum alkaloids and aminopyrine (internal standard) was performed on an InertSustain® C18 column, and the quantification of the analytes was performed on a 4000Q ultra-fast LC-MS/MS system with turbo ion spray source in the positive ion and multiple-reaction monitoring mode. Absolute recoveries ranged within 65.06-85.1% for plasma samples. The intra- and interday precision and accuracy of analytes were satisfactory. The methods were validated with sensitivity reaching the lower LOQ for aconitine, mesaconitine, hypaconitine, benzoylaconine, benzoylmesaconine, and benzoylhypaconine, which were 0.025, 0.025, 0.050, 0.025, 0.025, and 0.100 ng/mL, respectively. The method was successfully applied to a pharmacokinetic study of six Aconitum alkaloids in rat plasma after oral administration of crude ethanol extracts from the raw root of Aconitum kusnezoffii Reichb. by three different extraction processes. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
-
Chen, Ya-Yen; Chen, Chiao-Ming; Chao, Pi-Yu; Chang, Tsan-Ju; Liu, Jen-Fang
2005-01-01
AIM: To evaluate the effects of frying oil and Houttuynia cordata Thunb (H. cordata), a vegetable traditionally consumed in Taiwan, on the xenobiotic-metabolizing enzyme system of rodents. METHODS: Forty-eight Sprague-Dawley rats were fed with a diet containing 0%, 2% or 5% H. cordata powder and 15% fresh soybean oil or 24-h oxidized frying oil (OFO) for 28 d respectively. The level of microsomal protein, total cytochrome 450 content (CYP450) and enzyme activities including NADPH reductase, ethoxyresorufin O-deethylase (EROD), pentoxyresorufin O-dealkylase (PROD), aniline hydroxylase (ANH), aminopyrine demethylase (AMD), and quinone reductase (QR) were determined. QR represented phase II enzymes, the rest of the enzymes tested represented phase I enzymes. RESULTS: The oxidized frying oil feeding produced a significant increase in phase I and II enzyme systems, including the content of CYP450 and microsomal protein, and the activities of NADPH reductase, EROD, PROD, ANH, AMD and QR in rats (P<0.05). In addition, the activities of EROD, ANH and AMD decreased and QR increased after feeding with H. cordata in OFO-fed group (P<0.05). The feeding with 2% H. cordata diet showed the most significant effect. CONCLUSION: The OFO diet induces phases I and II enzyme activity, and the 2% H. cordata diet resulted in a better regulation of the xenobiotic-metabolizing enzyme system. PMID:15637750
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Martino, P.E.; Diaz Gomez, M.I.; Tamayo, D.
1988-01-01
Outbreaks of liver necrosis and liver hemangiosarcoma were detected in a mink breeding colony in Argentina. Analysis of the Minks' food revealed the presence of 2.6 ppm dimethylnitrosamine (NDMA) in it, apparently as a result of the addition of nitrite as preservative. Previous studies gave evidence of the particular susceptibility of minks to NDMA and other hepatic insults. The authors have determined several biochemical parameters known to correlate with NDMA hepatotoxic effects and compared with them those in rat liver. NDMA administration to both species resulted in the formation of reactive metabolites able to interact with liver DNA to givemore » N/sup 7/-methylguanine and O/sup 6/-methylguanine adducts. Biotransformation of NDMA by liver slices to CO/sub 2/ was significantly lower in the mink than in the rat, whereas the covalent binding (CB) to nucleic acids was slightly lower than in the rat. Aminopyrine N-demethylase activity was also significantly less in mink than in rat liver. The CB of NDMA reactive metabolites to microsomal proteins was not significantly lower in mink as compared to the rat, and the same holds true for the biotransformation of NDMA to formaldehyde by microsomal preparations. Results suggest that the high susceptibility of minks to NDMA might be partially due to a decreased ability to detoxicate NDMA but also a higher intrinsic susceptibility of their liver cells to a given chemical insult.« less
-
Role of gap junctions on synchronization in human neocortical networks.
Gigout, S; Deisz, R A; Dehnicke, C; Turak, B; Devaux, B; Pumain, R; Louvel, J
2016-04-15
Gap junctions (GJ) have been implicated in the synchronization of epileptiform activities induced by 4-aminopyrine (4AP) in slices from human epileptogenic cortex. Previous evidence implicated glial GJ to govern the frequency of these epileptiform events. The synchrony of these events (evaluated by the phase unlocking index, PUI) in adjacent areas however was attributed to neuronal GJ. In the present study, we have investigated the effects of GAP-134, a recently developed specific activator of glial GJ, on both the PUI and the frequency of the 4AP-induced epileptiform activities in human neocortical slices of temporal lobe epilepsy tissue. To delineate the impact of GJ on spatial spread of synchronous activity we evaluated the effects of carbenoxolone (CBX, a non-selective GJ blocker) on the spread in three axes 1. vertically in a given cortical column, 2. laterally within the deep cortical layers and 3. laterally within the upper cortical layers. GAP-134 slightly increased the frequency of the 4AP-induced spontaneous epileptiform activities while leaving the PUI unaffected. CBX had no effect on the PUI within a cortical column or on the PUI in the deep cortical layers. CBX increased the PUI for long interelectrodes distances in the upper cortical layers. In conclusion we provide new arguments toward the role played by glial GJ to maintain the frequency of spontaneous activities. We show that neuronal GJ control the PUI only in upper cortical layers. Copyright © 2016 Elsevier B.V. All rights reserved.
-
Recovery from dispositional and pharmacodynamic tolerance after chronic pentobarbital treatment.
Okamoto, M; Rao, S N; Reyes, J; Rifkind, A B
1985-10-01
Recovery characteristics of dispositional and pharmacodynamic tolerances produced by chronic Na-pentobarbital treatment were studied. To study dispositional tolerance, the rate of disappearance of pentobarbital from blood was estimated by sequential blood sampling before and after chronic treatment and during 15 days of withdrawal after chronic treatment. Pentobarbital half-life values were compared with four representative cytochrome P-450-mediated hepatic microsomal mixed-function oxidase reactions: aminopyrine demethylase, benzo(a)pyrene hydroxylase, 7-ethoxycoumarin deethylase and 7-ethoxyresorufin deethylase and with the concentration of cytochrome P-450 in sequentially biopsied liver samples. Pharmacodynamic tolerance was evaluated by measuring the increase in pentobarbital blood concentration required to produce predetermined central nervous system functional depression ratings. The recovery from dispositional tolerance was more rapid than the recovery from pharmacodynamic tolerance. Thus, whereas cytochrome P-450 levels and pentobarbital elimination rates were increased to close to twice pretreatment values by chronic treatment, by about 2 week post-withdrawal the values had normalized. In contrast, pharmacodynamic tolerance persisted after no residual dispositional tolerance remained. The neuronal functions most sensitive to barbiturate (i.e., sedation and loss of fine motor coordination) exhibited a greater degree of pharmacodynamic tolerance than other functions; hence the recovery of these neuronal functions took a longer period of time for their recovery. However, the rates of recovery of pharmacodynamic tolerance at all levels of central nervous system function seemed relatively constant indicating that there are uniform readaptation mechanisms for all the central nervous systems functions.
-
[Growth in children with diabetes insipidus].
Morla Báez, E; Dorantes Alvarez, L M; Chavarría Bonequi, C
1980-01-01
Commercial preparations of vasopressin for the treatment of diabetes insipidus are not available in Mexico. Besides, the hormone is useless in the nephrogenic variety. In the department of Endocrinology at the Hospital Infantil de Mexico, a preparation containing hydrochlorothiazide, aminopyrine and potassium chloride, which reduces urinary volumes in about two thirds, is employed in all varieties of the disease. Growth in stature was investigated in 44 patients under treatment, attending the Endocrine Outpatient Clinic since 1967 for a period of 2 to 12 years. Clinical material included 29 males and 15 females. There were 23 idiopathic, 7 histiocytosis, 5 nephrogenic, 4 craniopharyngiomas, 2 psychogenic polydipsia, 2 traumatic and 1, as a sequel of tuberculous meningoencephalitis. Six idiopathic, 2 nephrogenic, 2 traumatic, 1 histiocytosis, and 1 psychogenic proceeded between percentiles 3 and 97, parallel to the nearest line of reference along the whole period of study. Two nephrogenic, 2 histiocytosis, 1 psychogenic, 1 post-meningoencephalitis and 14 idiopathic, grew below the third percentile, but parallel to it. One nephrogenic, 4 histiocytosis, 4 craniopharyngioma and 3 idiopathic progressively departed from the initial centile. Two of the latter had growth hormone deficiency, and 1 had been very irregularly treated. It is concluded that the therapy employed limits stature impairment but does not produce catch-up growth. Accordingly, it is proposed that the treatment of diabetes insipidus should be started as early as possible, and that if progress in stature is appreciably deteriorated, the presence of additional pathology should be suspected.
-
Pulmonary uptake of morphine (M)
DOE Office of Scientific and Technical Information (OSTI.GOV)
Roerig, D.L.; Bunke, S.S.; Kotrly, K.J.
Previously the authors reported less than 5% of M was taken up during the first pass through the human lung. The low uptake of this basic lipophilic amine was further investigated in a single pass isolated perfused rat lung (IPL) in comparison to uptake of radiolabelled H/sub 2/O, antipyrine (A), aminopyrine (AM), nicotine (N) and phenylethylamine (P). The IPL was perfused for 5 min with each drug (5nmol/ml) and effluent collected in 10 sec fractions. Pulmonary extraction was calculated using indocyanine green dye as a non-extractable reference indicator. Accumulation of all compounds in the IPL reached an apparent equilibrium withinmore » 4 min. At equilibrium lung/perfusate conc. ratios for H/sub 2/O, A, AM, N, P and M were 1.04, 0.84, 0.85, 1.44, 2.57 and 1.13 respectively. The time course of M uptake differed from the other compounds since initial extraction of M was low (23%) compared to 75%, 53%, 35%, 82% and 86% for H/sub 2/O, A, AM, N and P respectively. Also, the half time to equilibrium for M was longer (50 sec) compared to 18, 21, 26, 19 and 22 sec for H/sub 2/O, A, AM, N and P respectively. The low initial pulmonary extraction of M compared to these compounds followed by greater M extraction during the remainder of drug infusion suggests uptake mechanisms for M different than the flow limited uptake for water and other basic amine drugs.« less
-
Cai, Mei-Quan; Wang, Rong; Feng, Li; Zhang, Li-Qiu
2015-02-01
A simultaneous determination method of 14 multi-class pharmaceuticals using solid-phase extraction (SPE) followed by high-performance liquid chromatography-tandem mass spectrometer (HPLC-MS/MS) was established to measure the occurrence and distribution of these pharmaceuticals in tap water and a drinking water treatment plant (DWTP) in Beijing, China. Target compounds included seven anti-inflammatory drugs, two antibacterial drugs, two lipid regulation drugs, one antiepileptic drug, and one hormone. Limits of detection (LODs) and limits of quantitation (LOQs) ranged from 0.01 to 1.80 ng/L and 0.05 to 3.00 ng/L, respectively. Intraday and inter-day precisions, recoveries of different matrices, and matrix effects were also investigated. Of the 14 pharmaceutical compounds selected, nine were identified in tap water of Beijing downtown with the concentration up to 38.24 ng/L (carbamazepine), and the concentration levels of detected pharmaceuticals in tap water (<5 ng/L for most pharmaceuticals) were lower than previous studies in other countries. In addition, ten and six pharmaceuticals were measured in raw water and finished water at the concentration ranged from 0.10 to 16.23 and 0.13 to 17.17 ng/L, respectively. Five compounds were detected most frequently in DWTP, namely antipyrine, carbamazepine, isopropylantipyrine, aminopyrine, and bezafibrate. Ibuprofen was found to be the highest concentration pharmaceutical during DWTP, up to 53.30 ng/L. DWTP shows a positive effect on the removal of most pharmaceuticals with 81.2-99.5 % removal efficiencies, followed by carbamazepine with 55.4 % removal efficiency, but it has no effect for removing ibuprofen and bezafibrate.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Kim, Young C.; Yim, Hye K.; Jung, Young S.
2007-08-15
Injury to liver, resulting in loss of its normal physiological/biochemical functions, may adversely affect a secondary organ. We examined the response of the liver and kidney to chemical substances that require metabolic activation for their toxicities in mice with a preceding liver injury. Carbon tetrachloride treatment 24 h prior to a challenging dose of carbon tetrachloride or acetaminophen decreased the resulting hepatotoxicity both in male and female mice as determined by histopathological examination and increases in serum enzyme activities. In contrast, the renal toxicity of the challenging toxicants was elevated markedly in male, but not in female mice. Partial hepatectomymore » also induced similar changes in the hepatotoxicity and nephrotoxicity of a challenging toxicant, suggesting that the contrasting response of male liver and kidney was associated with the reduction of the hepatic metabolizing capacity. Carbon tetrachloride pretreatment or partial hepatectomy decreased the hepatic xenobiotic-metabolizing enzyme activities in both sexes but elevated the renal p-nitrophenol hydroxylase, p-nitroanisole O-demethylase and aminopyrine N-demethylase activities significantly only in male mice. Increases in Cyp2e1 and Cyp2b expression were also evident in male kidney. Castration of males or testosterone administration to females diminished the sex-related differences in the renal response to an acute liver injury. The results indicate that reduction of the hepatic metabolizing capacity induced by liver injury may render secondary target organs susceptible to chemical substances activated in these organs. This effect may be sex-specific. It is also suggested that an integrated approach should be taken for proper assessment of chemical hazards.« less
-
Ren, Xianyun; Wang, Zhuqing; Gao, Baoquan; Liu, Ping; Li, Jian
2017-04-01
Oxytetracycline (OTC) is the most commonly used antibiotics for bacterial treatment in crustacean farming in China, and because of their intensive use, the potential harmful effects on aquatic organisms are of great concern. The aim of this study was to investigate the effects of oxytetracycline (OTC) on the antioxidant system, detoxification progress, and biomolecule damage in Portunus trituberculatus larvae. In this study, larvae that belonged to four zoeal stages were exposed to four different concentrations of OTC (0, 0.3, 3, and 30 μg/L) for 3 days. The results showed that the exposure to OTC significantly suppressed the antioxidant system of, especially, zoea I (Z1) and zoea II (Z2) larvae. OTC inhibited the transcriptional expression of phase I (CYP2 and CYP3) and phase II detoxification genes (GST) in a dose-dependent manner and altered the expressions of their corresponding enzymes, namely, aminopyrine N-demethylase, erythromycin N-demethylase, and glutathione S-transferase. Moreover, 0.3 μg/L OTC activated the transcription of ATP-binding cassette (ABC) transporter subfamily B (ABCB) and subfamily G (ABCG) in the Z1 and Z2 larvae, while 3 and 30 μg/L OTC suppressed all of them. Additionally, malondialdehyde content exhibited a dose- and zoea-effect relationship to some extent, but no significant differences were observed in the F values of the Z3 and Z4 larvae, except for the 30 μg/L OTC treatment. Thus, the Z3 and Z4 larvae were less sensitive to OTC exposure than the Z1 and Z2 larvae. Copyright © 2017 Elsevier Ltd. All rights reserved.
-
Short-term inhalation toxicity of methanol, gasoline, and methanol/gasoline in the rat.
Poon, R; Chu, I; Bjarnason, S; Vincent, R; Potvin, M; Miller, R B; Valli, V E
1995-01-01
Four- to five-week-old male and female Sprague Dawley rats were exposed to vapors of methanol (2500 ppm), gasoline (3200 ppm), and methanol/gasoline (2500/3200 ppm, 570/3200 ppm) six hours per day, five days per week for four weeks. Control animals were exposed to filtered room air only. Depression in body weight gain and reduced food consumption were observed in male rats, and increased relative liver weight was detected in rats of both sexes exposed to gasoline or methanol/gasoline mixtures. Rats of both sexes exposed to methanol/gasoline mixtures had increased relative kidney weight and females exposed to gasoline and methanol/gasoline mixtures had increased kidney weight. Decreased serum glucose and cholesterol were detected in male rats exposed to gasoline and methanol/gasoline mixtures. Decreased hemoglobin was observed in females inhaling vapors of gasoline and methanol/gasoline at 570/3200 ppm. Urine from rats inhaling gasoline or methanol/gasoline mixtures had up to a fourfold increase in hippuric acid, a biomarker of exposure to the toluene constituent of gasoline, and up to a sixfold elevation in ascorbic acid, a noninvasive biomarker of hepatic response. Hepatic mixed-function oxidase (aniline hydroxylase, aminopyrine N-demethylase and ethoxyresorufin O-deethylase) activities and UDP-glucuronosyltransferase activity were elevated in rats exposed to gasoline and methanol/gasoline mixtures. Histopathological changes were confined to very mild changes in the nasal passages and in the uterus, where decreased incidence or absence of mucosal and myometrial eosinophilia was observed in females inhaling gasoline and methanol/gasoline at 570/3200 ppm. It was concluded that gasoline was largely responsible for the adverse effects, the most significant of which included depression in weight gain in the males, increased liver weight and hepatic microsomal enzyme activities in both sexes, and suppression of uterine eosinophilia. No apparent interactive effects
-
Effects of atrazine on cytochrome P450 enzymes of zebrafish (Danio rerio).
Dong, Xiaoli; Zhu, Lusheng; Wang, Jinhua; Wang, Jun; Xie, Hui; Hou, Xinxin; Jia, Wentao
2009-10-01
In this study, the effects of atrazine (2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine) in males and females of adult zebrafish (Danio rerio) were studied. The liver microsomal cytochrome P450 content, NADPH-P450 reductase, aminopyrine N-demethylase (APND), and erythromycin N-demethylase (ERND) activity were measured. Zebrafish were exposed to control and 3 treatments (0.01, 0.1, and 1 mg L(-1)) of atrazine for 5, 10, 15, 20, and 25 days. The results indicated that, within the range of test atrazine concentrations, either P450 content or P450 isozyme activities could be induced by atrazine. Compared to controls, P450 content was significantly increased at all atrazine concentrations at days 10, 15, and 20; thereafter, at day 25, all concentrations decreased to approximately the control levels, both in males and females. In addition, the strongest induction of P450 content was observed on day 15 in males and day 10 in females at treatment concentrations of 1 mg L(-1). NADPH-P450 reductase activities showed mild increase in males; however, the females exhibited significant induction on days 15, 20, and 25; especially, at concentrations of 0.01 mg L(-1), the induction level was consistently increased during the experiment. The inducements of APND and ERND in males were mainly observed on the days 5, 10, and 15, which showed less distinct induction, while significant induction was observed in cases of treatments during all days in females. In conclusion, atrazine induces P450 enzymes in zebrafish, and the effects may function as significant toxicity mechanisms in zebrafish. Additionally, it also confirms the importance of using a combined multi-time and multi-index diagnostic method to enhance the sensitivity and effectiveness of the indices adopted.
-
Fu, Yao; Li, Ming; Liu, Ci; Qu, Jian-Ping; Zhu, Wen-Jun; Xing, Hou-Juan; Xu, Shi-Wen; Li, Shu
2013-08-01
Chlorpyrifos (CPF) and atrazine (ATR) are the most widely used organophosphate insecticides and triazine herbicides, respectively, worldwide. This study aimed at investigating the effects of ATR, CPF and mixture on common carp gills following 40-d exposure and 40-d recovery experiments. Cytochrome P450 content, activities of aminopyrine N-demethylase (APND) and erythromycin N-demethylase (ERND) and the mRNA levels of the CYP1 family (CYP1A, CYP1B, and CYP1C) were determined. In total, 220 common carps were divided into eleven groups, and each group was treated with a specific concentration of ATR (4.28, 42.8 and 428 μg/L), CPF (1.16, 11.6 and 116 μg/L) or ATR-CPF mixture (1.13, 11.3 and 113 μg/L). The results showed that P450 content and activities of APND and ERND in fish exposed to ATR and mixture were significantly higher than those in the control group. After the 40-d recovery treatment (i.e., depuration), the P450 content and the activities of APND and ERND in fish decreased to the background levels. A similar tendency was also found in the mRNA levels of the CYP1 family (CYP1A, CYP1B, and CYP1C) in common carp gills. The CPF-treated fish showed no significant difference from the control groups, except for a significant CYP1C induction. These results indicated that CYP enzyme levels are induced by ATR but were only slightly affected by CPF in common carp gills. In addition, the ATR and CPF exposure showed an antagonistic effect on P450 enzymes in common carp gills. Copyright © 2013 Elsevier Inc. All rights reserved.
-
Koch, H; Demling, L
1976-02-27
The study has been carried out to ensure the positive evidence of the measurement of the gastric mucosal blood-flow with the aid of the thermocouple (heat-clearance technique). The experiments have shown that the suction pressure of 600 mm mercury column which was used to fix the Thermocouple to the mucosa was indispensable in order to assess the blood-flow in the entire depth of the mucosa. Changes in the mucosal blood-flow are measuured at the same rate in all quadrants of the gastric corpus. The measuring of the blood-flow of a well circumscribed area of the mucosa is therefore representative for the entire corpus. Vasopressin led to a significant reduction of the gastric mucosal blood-flow measured with heat-clearance as well aminopyrine-clearance. There was a linear correlation between the results of both methods. Vasopressin selectively reduces the blood-flow of the gastric mucosa but not of the submucosa, the muscular layer and the serosa. Therefore it seems to be probable that changes in mucosal blood-flow selectively can be measured with the aid of the thermocouple. After previous stimulation with pentagastrin neither mucosal blood-flow nor acid secretion of the stomach were influenced by the occlusion of the celiac artery by 25 %. The occlusion of the celiac artery by 50 % reduced significantly the pentagastrin-stimulated gastric mucosal blood-flow whereas the acid secretion was not influenced. Prostaglandin E1 at a dose rate of 2 mug/kg-h increased significantly arterial and mucosal blood-flow as well as acid secretion of the stomach. In comparison PGE1 administered at a dose rate of 4 mug/kg-h reduced significantly gastric mucosal blood-flow and gastric secretion. PGE1 at a dose rate of 8 mug/kg-h did not produce any significant changes in blood-flow and secretion. The results suggested that the changes of gastric secretion observed with PGE1 were the consequence of primary changes in the gastric mucosal blood-flow.
-
Díaz-Gil, Juan J; García-Monzón, Carmelo; Rúa, Carmen; Martín-Sanz, Paloma; Cereceda, Rosa M; Miquilena-Colina, María E; Machín, Celia; Fernández-Martínez, Amalia; García-Cañero, Rarael
2008-05-01
Liver growth factor (LGF), a mitogen for liver cells, behaves as an anti-fibrotic agent even in extrahepatic sites, but its mechanistic basis is unknown. We aimed to determine the intrahepatic expression pattern of key modulators of liver fibrosis in bile duct-ligated rats (BDL) after injection of LGF. BDL rats received either LGF (4.5 microg/ratXdose, two doses/week, at time 0 or 2 or 5w after operation, depending on the group (BDL+LGF groups, n=20) or saline (BDL+S groups, n=20). Groups were compared in terms of fibrosis (histomorphometry), liver function (aminopyrine breath test), matrix metalloproteinases MMP-2 and MMP-9, transforming growth factor beta 1 (TGF-beta1) and liver endoglin content (Western blotting), and serum tissue inhibitor of metalloproteinases 1 (TIMP-1) levels (ELISA). In BDL+LGF rats, the fibrotic index was significantly lower at 5w, p=0.006, and at 8w, p=0.04, than in BDL+S rats. Liver function values in BDL+LGF rats were higher than those obtained in BDL+S rats (80% at 5w and 79% at 8w, versus 38% and 29%, p<0.01, taking healthy controls as 100%). Notably, in BDL+LGF rats the intrahepatic expression levels of both MMPs were lower at 2w (MMP-2, p=0.03; MMP-9, p=0.05) and 5w (MMP-2, p=0.05, MMP-9, p=0.04). In addition, the hepatic TGF-beta1 level in BDL+LGF rats was lower at 2w (36%, p=0.008), 5w (50%) and 8wk (37%), whereas intrahepatic endoglin expression remained constant in all BDL rats studied. LGF ameliorates liver fibrosis and improves liver function in BDL rats. The LGF-induced anti-fibrotic effect is associated with a decreased hepatic level of MMP-2, MMP-9 and TGF-beta1 in fibrotic rats.
-
DOE Office of Scientific and Technical Information (OSTI.GOV)
Wilkes, J.M.; Kajimura, M.; Scott, D.R.
Isolated rabbit gastric glands were used to study the nature of the muscarinic cholinergic responses of parietal cells. Carbachol stimulation of acid secretion, as measured by the accumulation of aminopyrine, was inhibited by the M1 antagonist, pirenzepine, with an IC50 of 13 microM; by the M2 antagonist, 11,2-(diethylamino)methyl-1 piperidinyl acetyl-5,11-dihydro-6H-pyrido 2,3-b 1,4 benzodiazepin-6-one (AF-DX 116), with an IC50 of 110 microM; and by the M1/M3 antagonist, diphenyl-acetoxy-4-methylpiperidinemethiodide, with an IC50 of 35 nM. The three antagonists displayed equivalent IC50 values for the inhibition of carbachol-stimulated production of 14CO2 from radiolabeled glucose, which is a measure of the turnover of themore » H,K-ATPase, the final step of acid secretion. Intracellular calcium levels were measured in gastric glands loaded with FURA 2. Carbachol was shown to both release calcium from an intracellular pool and to promote calcium entry across the plasma membrane. The calcium entry was inhibitable by 20 microM La3+. The relative potency of the three muscarinic antagonists for inhibition of calcium entry was essentially the same as for inhibition of acid secretion or pump related glucose oxidation. Image analysis of the glands showed the effects of carbachol, and of the antagonists, on intracellular calcium were occurring largely in the parietal cell. The rise in cell calcium due to release of calcium from intracellular stores was inhibited by 4-DAMP with an IC50 of 1.7 nM, suggesting that the release pathway was regulated by a low affinity M3 muscarinic receptor or state; Ca entry and acid secretion are regulated by a high affinity M3 muscarinic receptor or state, inhibited by higher 4-DAMP concentrations, suggesting that it is the steady-state elevation of Ca that is related to parietal cell function rather than the (Ca)i transient.« less
-
Vitamin C. Biosynthesis, recycling and degradation in mammals.
Linster, Carole L; Van Schaftingen, Emile
2007-01-01
Vitamin C, a reducing agent and antioxidant, is a cofactor in reactions catalyzed by Cu(+)-dependent monooxygenases and Fe(2+)-dependent dioxygenases. It is synthesized, in vertebrates having this capacity, from d-glucuronate. The latter is formed through direct hydrolysis of uridine diphosphate (UDP)-glucuronate by enzyme(s) bound to the endoplasmic reticulum membrane, sharing many properties with, and most likely identical to, UDP-glucuronosyltransferases. Non-glucuronidable xenobiotics (aminopyrine, metyrapone, chloretone and others) stimulate the enzymatic hydrolysis of UDP-glucuronate, accounting for their effect to increase vitamin C formation in vivo. Glucuronate is converted to l-gulonate by aldehyde reductase, an enzyme of the aldo-keto reductase superfamily. l-Gulonate is converted to l-gulonolactone by a lactonase identified as SMP30 or regucalcin, whose absence in mice leads to vitamin C deficiency. The last step in the pathway of vitamin C synthesis is the oxidation of l-gulonolactone to l-ascorbic acid by l-gulonolactone oxidase, an enzyme associated with the endoplasmic reticulum membrane and deficient in man, guinea pig and other species due to mutations in its gene. Another fate of glucuronate is its conversion to d-xylulose in a five-step pathway, the pentose pathway, involving identified oxidoreductases and an unknown decarboxylase. Semidehydroascorbate, a major oxidation product of vitamin C, is reconverted to ascorbate in the cytosol by cytochrome b(5) reductase and thioredoxin reductase in reactions involving NADH and NADPH, respectively. Transmembrane electron transfer systems using ascorbate or NADH as electron donors serve to reduce semidehydroascorbate present in neuroendocrine secretory vesicles and in the extracellular medium. Dehydroascorbate, the fully oxidized form of vitamin C, is reduced spontaneously by glutathione, as well as enzymatically in reactions using glutathione or NADPH. The degradation of vitamin C in mammals is
-
Biondo, Thais Maíra A; Tanae, Mirtes M; Coletta, Eliana Della; Lima-Landman, Maria Teresa R; Lapa, Antonio J; Souccar, Caden
2011-06-22
Baccharis trimera (Less.) DC. (Asteraceae) is a species native to South America used in Brazilian folk medicine to treat gastrointestinal and liver diseases, kidney disorders and diabetes. Previous studies from this laboratory confirmed the antacid and antiulcer activities of the plant aqueous extract (AE) in rat and mouse models. To investigate the mechanisms involved in the antacid action of AE and isolated compounds from Baccharis trimera. AE was assayed in vivo in cold-restraint stress gastric ulcers and in pylorus-ligated mice. Nine fractions (F2-F10) previously isolated from AE were assayed in vitro on acid secretion measured as [(14)C]-aminopyrine ([(14)C]-AP) accumulation in rabbit gastric glands, and on gastric microsomal H(+), K(+)-ATPase preparations. Chlorogenic acids (F2, F3, F6, F7), flavonoids (F9), an ent-clerodane diterpene (F8) and a dilactonic neo-clerodane diterpene (F10) have been identified in these fractions. Intraduodenal injection of AE (1.0 and 2.0 g/kg) in 4h pylorus-ligated mice decreased the volume (20 and 50%) and total acidity (34 and 50%) of acid secretion compared to control values. Administered orally at the same doses AE protected against gastric mucosal lesions induced in mice by restraint at 4°C. Exposure of isolated rabbit gastric glands to fractions F8 (10-100 μM) and F9 (10-300 μg/ml) decreased the basal [(14)C]-AP uptake by 50 and 60% of control (Ratio=6.2±1.1), whereas the remaining fractions were inactive. In the presence of the secretagogues F2 and F4 (30-300 μg/ml) decreased the [(14)C]-AP uptake induced by histamine (His) with a 100-fold lower potency than that of ranitidine. F5 and F6 reduced the [(14)C]-AP uptake stimulated by carbachol (CCh), but they were 10 to 20-fold less potent than atropine. F8 (diterpene 2) and F9 (flavonoids) decreased both the His- and CCh-induced [(14)C]-AP uptake, whereas F10 (diterpene 1) was inactive against the [(14)C]-AP uptake stimulated by secretagogues. Diterpene 2 was the most
-
Amended final report of the safety assessment of Drometrizole as used in cosmetics.
2008-01-01
Drometrizole is used in cosmetics as an ultraviolet (UV) light absorber and stabilizer. In an earlier safety assessment, the available data were found insufficient to support the safety of this ingredient, but new data have been provided and assessed. In voluntary industry reports to the Food and Drug Administration, this ingredient is reported to be used in noncoloring hair care products, and in an industry use concentration survey, uses in nail care products at 0.07% were reported. Drometrizole has absorbance maxima at 243, 298, and 340 nm. Drometrizole is used widely as a UV absorber and stabilizer in plastics, polyesters, celluloses, acrylates, dyes, rubber, synthetic and natural fibers, waxes, detergent solutions, and orthodontic adhesives. It is similarly used in agricultural products and insecticides. Drometrizole is approved as an indirect food additive for use as an antioxidant and/or stabilizer in polymers. Short-term studies using rats reported liver weight increases, increases in the activities of enzymes aminopyrine N-demethylase, and UDP glucuronosyl transferase, but no significant effects were noted in the activities of acid hydrolases or in hepatocyte organelles. Although Drometrizole is insoluble in water and soluble in a wide range of organic solvents, a distribution and elimination study using rats indicated that some Drometrizole was absorbed, then metabolized and excreted in the urine. Drometrizole and products containing Drometrizole were nontoxic in acute oral, inhalation, and dermal studies using animals. No increase in mortality or local and/or systemic toxicity were observed in a 13-week oral toxicity study using dogs; the no observed effect level (NOEL) was 31.75 mg/kg day(- 1) for males and 34.6 mg/kg day(-1) for females. In a 2-year feeding study using rats, a NOEL of 47 to 58 mg/kg day(- 1) was reported. Developmental studies of Drometrizole in rats and mice found no teratogenic effects and a NOEL of 1000 mg/kg day(- 1) was reported