Resveratrol protects against arsenic trioxide-induced nephrotoxicity by facilitating arsenic metabolism and decreasing oxidative stress.

Arsenic trioxide (As(2)O(3)) is an environmental toxicant and a potent antineoplastic agent. Exposure to arsenic causes renal cancer. Resveratrol is a well-known polyphenolic compound that is reported to reduce As(2)O(3)-induced cardiotoxicity. The present study aimed to investigate the effect of resveratrol on As(2)O(3)-induced nephrotoxicity and arsenic metabolism. Chinese Dragon-Li cats were injected with 1 mg/kg As(2)O(3) on alternate days; resveratrol (3 mg/kg) was administered via the forearm vein 1 h before the As(2)O(3) treatment. On the sixth day, the cats were killed to determine the histological renal damage, renal function, the accumulation of arsenic, and antioxidant activities in the kidney. Urine samples were taken for arsenic speciation. In the resveratrol + As(2)O(3)-treated group, activities of glutathione peroxidase, catalase, and superoxide dismutase, the ratio of reduced glutathione to oxidized glutathione, the total arsenic concentrations, and the percentage of methylated arsenic in urine were significantly increased. The concentrations of renal malondialdehyde, reactive oxygen species, 8-hydroxydeoxyguanosine, serum creatinine, blood urea nitrogen, and renal arsenic accumulation were significantly decreased and reduced renal morphologic injury was observed compared with the As(2)O(3)-treated group. These results demonstrate that resveratrol could significantly scavenge reactive oxygen species, inhibit As(2)O(3)-induced oxidative damage, and significantly attenuate the accumulation of arsenic in renal tissues by facilitating As(2)O(3) metabolism. These data suggest that use of resveratrol as postremission therapy for acute promyelocytic leukemia as well as adjunctive therapy in patients with exposure to arsenic may decrease arsenic nephrotoxicity.

Arsenic methylation metabolism and liver injury of acute promyelocytic leukemia patients undergoing arsenic trioxide treatment.

Although arsenic is effective in the treatment of acute promyelocytic leukemia (APL), as a well-known environmental toxicant, the side effects of arsenic treatment and arsenic methylation metabolism of the patients are rarely reported. In this manuscript, we investigated 23 APL patients treated with 10 mg arsenic trioxide daily, detected the arsenic metabolites in urine samples collected on the 0, 10th, and 20th day of arsenic treatment. At the same time, liver function and blood routine examination were also investigated in these APL patients. We found that, urinary monomethylated arsenic proportion (MMA%) increased, but dimethylated arsenic proportion (DMA%), the first methylation ratio (FMR) and the secondary methylation ratio (SMR) decreased with consecutive administration of arsenic trioxide. After adjustment for age impact, no statistical difference was observed in urinary arsenic concentrations and arsenic methylation capacity between male and female at the same treatment time point. During arsenic trioxide treatment of APL, transient elevation of serum aminotransferases was found in the blood samples, which indicated that liver injury occurred and probably reversible. Leukocytosis developed in 5 of the 23 patients with the administration of arsenic trioxide. No statistical difference was observed in the other blood routine examination parameters. These results demonstrated that the capacity of arsenic methylation decreased and transient liver injury occurred during arsenic trioxide treatment of APL, which indicated that the side effects of clinical arsenic treatment can not be ignored.

Altered arsenic disposition in experimental nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is represented by a spectrum of liver pathologies ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Liver damage sustained in the progressive stages of NAFLD may alter the ability of the liver to properly metabolize and eliminate xenobiotics. The purpose of the current study was to determine whether NAFLD alters the disposition of the environmental toxicant arsenic. C57BL/6 mice were fed either a high-fat or a methionine-choline-deficient diet to model simple steatosis and NASH, respectively. At the conclusion of the dietary regimen, all mice were given a single oral dose of either sodium arsenate or arsenic trioxide. Mice with NASH excreted significantly higher levels of total arsenic in urine (24 h) compared with controls. Total arsenic in the liver and kidneys of NASH mice was not altered; however, NASH liver retained significantly higher levels of the monomethyl arsenic metabolite, whereas dimethyl arsenic was retained significantly less in the kidneys of NASH mice. NASH mice had significantly higher levels of the more toxic trivalent form in their urine, whereas the pentavalent form was preferentially retained in the liver of NASH mice. Moreover, hepatic protein expression of the arsenic biotransformation enzyme arsenic (3+ oxidation state) methyltransferase was not altered in NASH animals, whereas protein expression of the membrane transporter multidrug resistance-associated protein 1 was increased, implicating cellular transport rather than biotransformation as a possible mechanism. These results suggest that NASH alters the disposition of arsenical species, which may have significant implications on the overall toxicity associated with arsenic in NASH.

Speciation of arsenic in urine following intravenous administration of arsthinol in mice.

Recent investigations have shown that arsthinol, a trivalent organoarsenic compound (dithiarsolane), has been active in vitro on leukemia cell lines and offers a better therapeutic index than arsenic trioxide, as estimated by the ratio LD50/IC50. To complete our understanding of its urinary excretion, a sensitive method using liquid chromatography coupled with mass spectrometry (LC-MS) was used. Mice were injected intravenously with a single dose of arsthinol at 0.2 mmol/kg of body weight. The amount of total arsenic in tissues and body fluids was determined by a colorimetric method and urine metabolites were analyzed on a C18 Acclaim PepMap 100 A column by LC-MS. Our results showed that only three arsenic species (acetarsol, acetarsol oxide and arsthinol) were detected in the first 24-h urine. Overall, this study confirms that the hydrolysis of dithiarsolanes to arsenoxides (i.e. acetarsol oxide) can be followed by an oxidation in arsonic acids (i.e. acetarsol). All these compounds are excreted in the urine.

A Simultaneous Mixed-Effects Pharmacokinetic Model for Nefopam, N-desmethylnefopam, and Nefopam N-Oxide in Human Plasma and Urine.

BACKGROUND AND OBJECTIVE: Nefopam is a non-opioid, non-steroidal, central analgesic thought to act via multiple mechanisms including potent inhibition of serotonin-norepinephrine reuptake and modulation of voltage-sensitive calcium and sodium channels. There has been a resurgence in its use for postoperative pain and neuropathic pain. Dosing route-dependent metabolism and clinical effects have been described following intravenous and oral nefopam. N-desmethylnefopam and nefopam N-oxide are metabolites of clinical interest. We sought to develop a joint pharmacokinetic model to simultaneously describe the plasma and urinary pharmacokinetics of nefopam and the two metabolites following an oral pharmacological dose of [14C]-nefopam to healthy volunteers, and to estimate inter-individual variability in their pharmacokinetics. METHODS: Pharmacokinetic data for the parent and metabolites were analyzed simultaneously using NONMEM® (nonlinear mixed-effect modeling) v7.3. The modeling process evaluated, in part, one- and two-compartment linear pharmacokinetic models for nefopam and a single compartment for each of the two metabolites. Pathways for presystemic metabolism of both metabolites were explored. RESULTS: The final structural model simultaneously described the plasma and urinary pharmacokinetics of nefopam and the two metabolites. It consists of a central compartment for nefopam and for each of the two metabolites, as well as a peripheral compartment for the parent, and the associated urine compartments. The rapid formation and appearance of the N-oxide in plasma, characterized by concentrations that peak earlier than the parent, could be described by presystemic formation in the gastrointestinal tract. CONCLUSIONS: A descriptive, robust and predictive parent-metabolite model has been developed using a population mixed-effects approach to characterize the pharmacokinetics of nefopam and its metabolites simultaneously in healthy subjects following oral administration of nefopam. The model may be used for dose selection, analysis of sparse data, identification of intrinsic and extrinsic factors, and to model the clinical effects of each analyte.

Toxicological assessment of nano and micron-sized tungsten oxide after 28days repeated oral administration to Wistar rats.

Tungsten oxide (WO3) nanoparticles (NPs) are being used in various applications. However, the health consequences of WO3 NPs exposure have not been explored extensively. Hence, the goal of this study was to evaluate the toxicity of WO3 NPs and their microparticles (MPs) after 28days repeated oral administration in Wistar rats. The particles were characterised by transmission electron microscopy (TEM), dynamic light scattering (DLS), laser Doppler velocimetry (LDV), Brunner-Emmett-Teller (BET), X- ray diffraction (XRD), and inductively coupled plasma optical emission spectrometer (ICP-OES). Genotoxicity was determined using comet assay in blood and liver and micronucleus test in bone marrow. Biochemical parameters such as aspartate aminotransferase and alanine aminotransferase in serum and reduced glutathione content, catalase and lipid peroxidation in liver tissue were determined. Histopathological changes in tissues were documented. Biodistribution of tungsten (W) in rat's blood, urine, feces and tissues were analysed. The mean size of WO3 NPs and MPs by TEM was 52±2.97nm, and 5.73±7.58µm and morphology were spherical in both the particles. DLS of NPs was 195.6nm. XRD and BET data of WO3 NPs and MPs showed a hexagonal and tetragonal crystal structure and surface area of 19.33 and 15.15(m2/g), respectively. The results revealed a significant increase in DNA damage and micronuclei, a difference in biochemical levels and histopathological alterations after exposure to 1000mg/kg dose of WO3 NPs. W biodistribution was detected in all the tissues in a dose and organ-dependent manner in both the particles. The highest amount of W was found in the liver and lowest in the brain of the treated rats. The tested NPs were found to have little toxicity hazard.

Direct Quantification of Rare Earth Elements Concentrations in Urine of Workers Manufacturing Cerium, Lanthanum Oxide Ultrafine and Nanoparticles by a Developed and Validated ICP-MS.

Rare earth elements (REEs) have undergone a steady spread in several industrial, agriculture and medical applications. With the aim of exploring a sensitive and reliable indicator of estimating exposure level to REEs, a simple, accurate and specific ICP-MS method for simultaneous direct quantification of 15 REEs ((89)Y, (139)La, (140)Ce, (141)Pr, (146)Nd, (147)Sm, (153)Eu, (157)Gd, (159)Tb, (163)Dy, (165)Ho, (166)Er, (169)Tm, (172)Yb and (175)Lu) in human urine has been developed and validated. The method showed good linearity for all REEs in human urine in the concentrations ranging from 0.001-1.000 µg ∙ L(-1) with r² > 0.997. The limits of detection and quantification for this method were in the range of 0.009-0.010 µg ∙ L(-1) and 0.029-0.037 µg ∙ L(-1), the recoveries on spiked samples of the 15 REEs ranged from 93.3% to 103.0% and the relative percentage differences were less than 6.2% in duplicate samples, and the intra- and inter-day variations of the analysis were less than 1.28% and less than 0.85% for all REEs, respectively. The developed method was successfully applied to the determination of 15 REEs in 31 urine samples obtained from the control subjects and the workers engaged in work with manufacturing of ultrafine and nanoparticles containing cerium and lanthanum oxide. The results suggested that only the urinary levels of La (1.234 ± 0.626 µg ∙ L(-1)), Ce (1.492 ± 0.995 µg ∙ L(-1)), Nd (0.014 ± 0.009 µg ∙ L(-1)) and Gd (0.023 ± 0.010 µg ∙ L(-1)) among the exposed workers were significantly higher (p < 0.05) than the levels measured in the control subjects. From these, La and Ce were the primary components, and accounted for 88% of the total REEs. Lanthanum comprised 27% of the total REEs while Ce made up the majority of REE content at 61%. The remaining elements only made up 1% each, with the exception of Dy which was not detected. Comparison with the previously published data, the levels of urinary La and Ce in workers and the control subjects show a higher trend than previous reports.

Metabolism and urinary disposition of N,N-dimethyltryptamine after oral and smoked administration: a comparative study.

N,N-dimethyltryptamine (DMT) is a widely distributed plant alkaloid that displays partial agonist activity at the 5-HT2A receptor and induces intense psychedelic effects in humans when administered parenterally. However, self-administration studies have reported a total lack of activity following oral intake. This is thought to be due to extensive degradation by monoamine oxidase (MAO). Despite increased use of DMT and DMT-containing preparations, such as the plant tea ayahuasca, the biotransformation of DMT in humans when administered alone is relatively unknown. Here we used high performance liquid chromatography (HPLC)/electrospray ionization (ESI)/selected reaction monitoring (SRM)/tandem mass spectrometry (MS/MS) to characterize the metabolism and disposition of oral and smoked DMT. Twenty-four-hour urine samples were obtained from 6 DMT users before and after intake of 25 mg DMT doses on two separate sessions. In one session, DMT was taken orally and in another it was smoked. After oral ingestion, no psychotropic effects were experienced and no DMT was recovered in urine. MAO-dependent indole-3-acetic acid (IAA) represented 97% of the recovered compounds, whereas DMT-N-oxide (DMT-NO) accounted for only 3%. When the smoked route was used, the drug was fully psychoactive, unmetabolized DMT and DMT-NO rose to 10% and 28%, respectively, and IAA levels dropped to 63%. An inverse correlation was found between the IAA/DMT-NO ratio and subjective effects scores. These findings show that in the smoked route a shift from the highly efficient MAO-dependent to the less efficient CYP-dependent metabolism takes place. This shift leads to psychoactivity and is analogous to that observed in ayahuasca preparations combining DMT with MAO inhibitors.

Disposition of methadone in methadone maintenance.

Six detoxified opiate addicts housed in a closed metabolic ward received methadone in stepwise increasing doses of 10, 20, 40, and 80 mg/day during 1 month. Four were given 14C-methadone at the lowest dose and again at the highest dose. Of the subjects receiving radiomethadone, 2 excreted the major part of the radioactivity in urine and 2 about equally in urine and feces. In addition to methadone, 7 metabolites were isolated and identified in urine and 3 metabolites in feces. About 75% of the urinary and fecal radioactive metabolites were unconjugated. Urinary excretion of methadone and its major N-monomethylated metabolite accounted for 17% to 57% of the given dose. The ratio of metabolite to parent drug increased in 5 of 6 subjects, and the urinary recovery of unchanged methadone decreased during the period. The results indicate that enhanced demethylation of methadone may occur during oral administration to man.

Arsenic trioxide poisoning: a description of two acute overdoses.

Arsenic is a traditional poison that has a history extending back into ancient times, as a medicinal agent, a homicidal poison and more recently in deliberate and unintentional self-poisoning. We report two cases of acute poisoning with an unwettable formulation of arsenic trioxide. Both patients had early gastrointestinal toxicity and were treated with early whole bowel irrigation (WBI). Chelation therapy with dimercaptosuccinic acid (dimercaptosuccinate, DMSA) was commenced within 24 hours and serial blood and urine arsenic concentrations were measured. Neither patient suffered any adverse outcome in spite of very high blood and urine concentrations of arsenic. Arsenic quantification in blood, urine and faeces suggested that enhanced gastrointestinal decontamination was minimally effective for decontamination and that DMSA for at least two weeks was required.

A model for scaling the results of U excretion rate studies in beagle dogs to man.

A biokinetic model was used to simulate retention and excretion of two forms of U: ammonium diuranate (ADU), a relatively soluble form, and U3O8, a relatively insoluble form. These two U forms represent those most likely to be encountered in the U milling industry. The simulation model was compared with results from a study of aerosols of commercial refined U ore inhaled by laboratory animals. Beagle dogs were exposed by inhalation to ADU aerosols to achieve a median initial body burden of 0.058 mg U kg-1 body weight (within a range of 0.016 to 0.64 mg U kg-1), or to U3O8 aerosols to achieve a median retained body burden of 0.28 mg U kg-1 (0.030-0.81 mg U kg-1). The simulation model accurately described the accumulation of nephrotoxic concentrations of U in kidneys of animals exposed to ADU. Very small fractions of the initial body burden of U3O8 were translocated to kidney, and these fractions were overestimated by the model. The model showed general agreement with results of other laboratory animal studies and with available information from human exposures to ADU, UF6, or U3O8.

Studies on the metabolic pattern of propiverine in urine after single administration.

In 11 healthy volunteers the metabolic pattern of propiverine [1; alpha, alpha-diphenyl-n-propoxy-1, 2-acetic acid-4-(1-methyl-piperidinyl)ester] was studied in urine after a single i.v. (5 mg) or oral dose (15 mg). To each dose 30.4 microCi (1.11 MBq) 14C-1 were added. The various urine fractions (0-1, 1-4, 4-8, 8-24 h) were extracted by chloroform and ethyl acetate at different pH-values and TLC was performed. The metabolites were identified by comparison of the RF-values of the radiochromatograms with those of the reference compounds after TLC using various solvent mixtures. Evidence for identity of the metabolites was additionally obtained by ester hydrolysis, ether cleavage or reduction with subsequent TLC after elution of the spots from the plate. The formed products were rechromatographed. 1 undergoes an extensive biotransformation: about 70% of the radioactive substances in urine consisted of 19 different metabolites, while 1 amounted to only 3%. Additionally, 3 acidic metabolites of unknown structure were isolated. Due to the metabolic pattern the following reactions of degradation were found: oxidation of the tertiary nitrogen in the piperidinyl moiety yielding N-oxides (40 to 50% of radioactivity), oxidation of one of the three carbon atoms of the propyl side chain, oxidation of the N-methyl group resulting in N-demethylated products, and ester cleavage. Propiverine N-oxide (20 to 25%) was determined as a major metabolite, whereas demethylated products occurred in minute amounts (1%). There was no evidence for oxidation of both phenyl moieties.

Comparison of absorption after inhalation and instillation of uranium octoxide.

Values for the absorption parameters were compared after inhalation or intratracheal instillation of 1.5 microm mass median aerodynamic diameter (MMAD) 233U3O8 particles into the lungs of HMT strain rats. The two sets of parameter values were similar, as were the calculated dose coefficients and predicted biokinetics for workers. Hence the inhalation and instillation techniques can probably both be used to generate values of the absorption parameters for U3O8.

Two case studies of highly insoluble plutonium inhalation with implications for bioassay.

Two well characterised Pu inhalation cases show some remarkable similarities between substantially different types of Pu oxide. The circumstances of exposure, therapy, bioassay data, chemical solubility studies and dosimetry associated with these cases suggest that highly insoluble Pu may be more common than previously thought, and can pose significant challenges to bioassay programmes.

[Stress-related alteration of urine compositions: idiopathic CaOx stone formers, patients with chronic inflammatory bowel disease (CIBD) and healthy controls]. / Stressbedingte Alteration der Harnzusammensetzungen : Untersuchung von idiopathischen CaOx-Steinbildnern, Patienten mit chronisch entzündlicher Darmerkrankung und gesunden Probanden.

BACKGROUND: Increased emotional stress in everyday life influences the way of living and metabolism of people living in developed countries. Contemporaneously, the incidence and prevalence of urolithiasis rises. Does a pathogenetically relevant relationship exist between chronic stress burden and permanently altered urinary composition? PATIENTS AND METHODS: The influence of chronic stress burden on urine composition and risk of urinary calcium oxalate (CaOx) stone formation was, for the first time, comprehensively investigated in 29 healthy controls (CG), 29 idiopathic CaOx stone formers (SF) and 28 patients suffering from chronic inflammatory bowel disease (CIBD). After 4 days with standardized nutrition, 24-h urine was collected. Extensive urinalysis was performed and APCaOx index calculated. Evaluation of subjective stress level was carried out by using the standardized and well-established questionnaire Trierer Inventar zur Beurteilung von chronischem Stress (TICS). The concentration values of the urinary parameters as well as the APCaOx values were linearly correlated with the stress scores obtained from the different items of the TICS. A significance level p≤0.05 was considered to indicate statistical significance. RESULTS: The mean APCaOx indices amounted to 0.8±0.3 in CG, 1.2±0.7 in SF and 1.9±1.2 in CIBD. The increased APCaOx in SF mainly results from relatively increased Ca and oxalate excretions, whereas in CIBD this also results from reduced urinary excretions of citrate and Mg as well as reduced 24-h urinary volumes. The calculation of linear correlation coefficients between a TICS stress dimension and a concentration value of a urinary parameter or APCaOx results in r values not exceeding 0.600. However, some of these correlations are statistically highly significant. In SF only one combination with Ca was observed, while in CIBD in contrast a number of combinations, in particular including Na, was obtained. In CG direct statistical relationships between stress burden and citrate as well as Mg exist. In this group, increased stress burden is associated with increased inhibitory potential to prevent CaOx stone formation. CONCLUSION: In the investigated study groups, differently complex relationships between amount of stress burden and risk of CaOx stone formation were observed, however, without obvious physicochemical principle(s). In some individuals, stress can be associated with a significantly stress-related alteration of urinary composition towards increased CaOx stone formation risk. The results obtained from the CIBD group allow for the first time a conclusive link between emotional stress and inflammatory activity on the one hand and inflammatory activity and metabolic risk constellation of CaOx stone formation on the other hand.