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Sample records for administered dose excreted

  1. The urinary excretion of orally administered pteroyl-l-glutamic acid by the rat

    PubMed Central

    Blair, J. A.; Dransfield, E.

    1971-01-01

    1. The urinary excretion of folates after oral administration of [2-14C]pteroyl-l-glutamic acid was studied by assaying the radioactivity in the urine and in materials purified and characterized by t.l.c. 2. Radioactivity excreted was 6.8, 5.9 and 30.7% of the oral dose in the first 24h after doses of 3.1, 32 and 320μg/kg respectively. 3. Extensive decomposition of urinary folates to pteroyl-l-glutamic acid was prevented by antioxidants or collection of urine frozen. 4. At the three dosages, two major and one minor radioactive compounds were isolated. One of the major metabolites was 5-methyltetrahydropteroylglutamic acid. The others were unidentified but were not pteroylglutamic acid, 7,8-dihydro-, 5,6,7,8-tetrahydro-, 5- or 10-formyl-tetrahydro-, 5,10-methylidyne-tetrahydro-, 5-formimidoyl-tetrahydro-, 5,10-methylene-tetrahydro-, 5-methyltetrahydro-pteroylglutamic acid, nor any decomposition products of these compounds formed during isolation. Labelled unconjugated pteridines were absent. 5. Labelled pteroyl-l-glutamic acid was displaced by oral administration of unlabelled pteroyl-l-glutamic acid (1.6mg/kg) when given 3.5h after, but not when given 24h after the labelled dose. 6. The results show that orally administered [2-14C]pteroyl-l-glutamic acid is absorbed without metabolism and is then metabolized into naturally occurring tetrahydro-folates. 7. These findings are discussed with reference to previous work. PMID:5124394

  2. [Pharmacokinetics of cefatrizine administered in repeated doses].

    PubMed

    Couet, W; Reigner, B G; Lefebvre, M A; Bizouard, J; Fourtillan, J B

    1988-05-01

    Twelve healthy volunteers received cefatrizine orally at doses equal to 500 mg every 12 h for 5 days. Cefatrizine was assayed by high performance liquid chromatography in plasma and urines collected after the first and/or the last administration. Cefatrizine absorption was rapid; its peak plasma level was reached at time 1.79 +/- 0.07 h following the first dose, it was equal to 7.37 +/- 0.31 micrograms.ml-1. Its apparent elimination half-life was equal to 1.50 +/- 0.05 h, it explains the lack of accumulation with time during multiple administrations every 12 hours. Comparisons between peak plasma concentration and area under curves following the first and last dosing showed significant (p less than 0.01) but weak (close to 15%) reduction of these 2 parameters with time which could be explained by a slight reduction of cefatrizine absorption with time. In conclusion, cefatrizine does not accumulate when administered repeatedly at a dose equal to 500 mg every 12 h in young adult, and its pharmacokinetics is virtually linear with time. PMID:3043350

  3. Dose Ranging, Expanded Acute Toxicity and Safety Pharmacology Studies for Intravenously Administered Functionalized Graphene Nanoparticle Formulations

    PubMed Central

    Kanakia, Shruti; Toussaint, Jimmy; Chowdhury, Sayan Mullick; Tembulkar, Tanuf; Lee, Stephen; Jiang, Ya-Ping; Lin, Richard Z.; Shroyer, Kenneth R.; Moore, William; Sitharaman, Balaji

    2014-01-01

    Graphene nanoparticles dispersions show immense potential as multifunctional agents for in vivo biomedical applications. Herein, we follow regulatory guidelines for pharmaceuticals that recommend safety pharmacology assessment at least 10 – 100 times higher than the projected therapeutic dose, and present comprehensive single dose response, expanded acute toxicology, toxicokinetics, and respiratory/cardiovascular safety pharmacology results for intravenously administered dextran-coated graphene oxide nanoplatelet (GNP-Dex) formulations to rats at doses between 1–500 mg/kg. Our results indicate that the maximum tolerable dose (MTD) of GNP-Dex is between 50 mg/kg ≤ MTD < 125 mg/kg, blood half-life < 30 minutes, and majority of nanoparticles excreted within 24 hours through feces. Histopathology changes were noted at ≥ 250 mg/kg in the heart, liver, lung, spleen, and kidney; we found no changes in the brain and no GNP-Dex related effects in the cardiovascular parameters or hematological factors (blood, lipid, and metabolic panels) at doses < 125 mg/kg. The results open avenues for pivotal preclinical single and repeat dose safety studies following good laboratory practices (GLP) as required by regulatory agencies for investigational new drug (IND) application. PMID:24854092

  4. Potassium Bicarbonate Supplementation Lowers Bone Turnover and Calcium Excretion in Older Men and Women: A Randomized Dose-Finding Trial

    PubMed Central

    Dawson-Hughes, Bess; Harris, Susan S; Palermo, Nancy J; Gilhooly, Cheryl H; Shea, M Kyla; Fielding, Roger A; Ceglia, Lisa

    2016-01-01

    The acid load accompanying modern diets may have adverse effects on bone and muscle metabolism. Treatment with alkaline salts of potassium can neutralize the acid load, but the optimal amount of alkali is not established. Our objective was to determine the effectiveness of two doses of potassium bicarbonate (KHCO3) compared with placebo on biochemical markers of bone turnover, and calcium and nitrogen (N) excretion. In this double-blind, randomized, placebo-controlled study, 244 men and women age 50 years and older were randomized to placebo or 1 mmol/kg or 1.5 mmol/kg of KHCO3 daily for 3 months; 233 completed the study. The primary outcomes were changes in 24-hour urinary N-telopeptide (NTX) and N; changes in these measures were compared across the treatment groups. Exploratory outcomes included 24-hour urinary calcium excretion, serum amino-terminal propeptide of type I procollagen (P1NP), and muscle strength and function assessments. The median administered doses in the low-dose and high-dose groups were 81 mmol/day and 122 mmol/day, respectively. When compared with placebo, urinary NTX declined significantly in the low-dose group (p =0.012, after adjustment for baseline NTX, gender, and change in urine creatinine) and serum P1NP declined significantly in the low-dose group (p =0.004, adjusted for baseline P1NP and gender). Urinary calcium declined significantly in both KHCO3 groups versus placebo (p < 0.001, adjusted for baseline urinary calcium, gender, and changes in urine creatinine and calcium intake). There was no significant effect of either dose of KHCO3 on urinary N excretion or on the physical strength and function measures. KHCO3 has favorable effects on bone turnover and calcium excretion and the lower dose appears to be the more effective dose. Long-term trials to assess the effect of alkali on bone mass and fracture risk are needed. PMID:25990255

  5. Anthocyanin excretion increases linearly with increasing strawberry dose.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A clinical study was conducted to investigate the dose response and metabolism of strawberry anthocyanins. In a crossover study design, twelve healthy adults consumed each of three strawberry treatments. The treatments were 100 g, 200 g, and 400 g of pureed strawberries, delivering 15 micromol, 30 m...

  6. EFFECT OF DOSE ON THE EXCRETION AND METABOLISM OF MONOMETHYLARSONIC ACID IN THE MOUSE

    EPA Science Inventory

    EFFECT OF DOSE ON THE EXCRETION AND METABOLISM OF MONOMETHYLARSONIC ACID IN THE MOUSE
    M F Hughes1, V Devesa2, B C Edwards1, C T Mitchell1, E M Kenyon1, and D J Thomas1. 1US EPA, ORD, NHEERL, ETD, Research Triangle Park, NC; 2UNC-CH, CEMALB, Chapel Hill, NC

    Monomethylar...

  7. Hippuric acid excretion after benzylamine ingestion in man.

    PubMed Central

    Wood, S G; Al-Ani, M R; Lawson, A

    1978-01-01

    The fate of 14C-benzylamine after oral administration as the hydrochloride has been investigated in two male volunteers. Over 98% of the administered radiolabel was excreted in the urine as 14C-hippuric acid within 24 hours. The rate of urinary hippuric acid excretion was extremely rapid, with more than 90% of the dose excreted after three hours. PMID:698137

  8. Novel type of ornithine-glutathione double conjugate excreted as a major metabolite into the bile of rats administered clebopride

    SciTech Connect

    Ishizuka, T.; Komiya, I.; Hiratsuka, A.; Watabe, T. )

    1990-06-01

    Rats orally given radioactive Clebopride ((14C)CP; N-(1'-benzyl-4'-piperidyl)-2-(14C)methoxy-4-amino-5-chlorobenzamide++ +), an antiulcer agent, excreted a novel type of ornithine (Orn)-GSH double conjugate in the bile as a major metabolite ((14C)BMCP), corresponding to 18% of the dose. The present study provides the first evidence for Orn conjugation of a xenobiotic in mammals and demonstrates that the structure of the radioactive conjugate differs fundamentally from those known in birds and reptiles. The structure of the biliary metabolite, (14C)BMCP, purified to homogeneity by silica gel thin layer and reverse phase high pressure liquid chromatography, was elucidated as S-(2-ornithylamino-4-(14C)methoxy-5-(1'-methyl-4'-piperidylamin o) carboxyphenyl)glutathione, based mainly on the following facts: (1) BMCP showed a protonated molecular ion (M + H)+ peak at m/z 683 in the secondary ion mass spectrum and (2) (14C)BMCP afforded Orn, glutamic acid, glycine, S-(2-amino-4-(14C)methoxy-5-carboxyphenyl)cysteine (( 14C)AMCC), and 1-methyl-4-aminopiperidine (MAP) quantitatively, in an equal molar ratio, by complete hydrolysis with peptidase. Thus, BMCP was a metabolite with three enzymatically hydrolyzable amide bonds in addition to the one existing originally in the parent structure of the drug, which produces MAP by peptic digestion. Of the three additional amide bonds of BMCP, one was a novel type of bond formed by condensation of the alpha-carboxylic acid group of Orn with the primary aromatic amino group of the drug and the other two were in the S-glutathionyl residue, substituted for the chlorine atom vicinal to the Orn-conjugating primary amino group in the aromatic ring and affording glutamic acid, glycine, and the S-cysteine conjugate AMCC by hydrolysis of BMCP with the peptidase.

  9. Cystatin C as a potential biomarker for dosing of renally excreted drugs

    PubMed Central

    Brou, Nguessan Aimé; Jacqz-Aigrain, Evelyne; Zhao, Wei

    2015-01-01

    The objective of the present study was to review the available pharmacokinetic evidence for the utility of cystatin C (CysC) as a marker of renal function to predict the dose of renally excreted drugs.The bibliographic search used PubMed and EMBASE databases, from its inception through to January 2014, with the following keywords ‘pharmacokinetics’ and ‘cystatin C’.Sixteen pharmacokinetic publications were identified and seven drugs primarily excreted by the kidney were studied. Among them, only one study was performed in children, the others were performed in adults and/or elderly subjects, either healthy volunteers or patients with variable clinical conditions, such as cystic fibrosis and cancer. Most of studies (n = 13/16) demonstrated that CysC was better correlated with clearance/trough concentration of evaluated drugs compared with creatinine.Our review supports that CysC is a good marker of renal function to predict dose of renally excreted drugs. Efforts should be made to evaluate the impact of CysC in special populations in order to define its clinical value in dosing optimization. PMID:25655191

  10. Subchronic chloroform priming protects mice from a subsequently administered lethal dose of chloroform

    SciTech Connect

    Philip, Binu K.; Anand, Sathanandam S.; Palkar, Prajakta S.; Mumtaz, Moiz M.; Latendresse, John R.; Mehendale, Harihara M. . E-mail: mehendale@ulm.edu

    2006-10-01

    Protection offered by pre-exposure priming with a small dose of a toxicant against the toxic and lethal effects of a subsequently administered high dose of the same toxicant is autoprotection. Although autoprotection has been extensively studied with diverse toxicants in acute exposure regimen, not much is known about autoprotection after priming with repeated exposure. The objective of this study was to investigate this concept following repeated exposure to a common water contaminant, chloroform. Swiss Webster (SW) mice, exposed continuously to either vehicle (5% Emulphor, unprimed) or chloroform (150 mg/kg/day po, primed) for 30 days, were challenged with a normally lethal dose of chloroform (750 mg chloroform/kg po) 24 h after the last exposure. As expected, 90% of the unprimed mice died between 48 and 96 h after administration of the lethal dose in contrast to 100% survival of mice primed with chloroform. Time course studies indicated lower hepato- and nephrotoxicity in primed mice as compared to unprimed mice. Hepatic CYP2E1, glutathione levels (GSH), and covalent binding of {sup 14}C-chloroform-derived radiolabel did not differ between livers of unprimed and primed mice after lethal dose exposure, indicating that protection in liver is neither due to decreased bioactivation nor increased detoxification. Kidney GSH and glutathione reductase activity were upregulated, with a concomitant reduction in oxidized glutathione in the primed mice following lethal dose challenge, leading to decreased renal covalent binding of {sup 14}C-chloroform-derived radiolabel, in the absence of any change in CYP2E1 levels. Buthionine sulfoximine (BSO) intervention led to 70% mortality in primed mice challenged with lethal dose. These data suggest that higher detoxification may play a role in the lower initiation of kidney injury observed in primed mice. Exposure of primed mice to a lethal dose of chloroform led to 40% lower chloroform levels (AUC{sub 15-360min}) in the systemic

  11. Does administering iodine in radiological procedures increase patient doses?

    SciTech Connect

    He, Wenjun; Yao, Hai; Huda, Walter; Mah, Eugene

    2014-11-01

    Purpose: The authors investigated the changes in the pattern of energy deposition in tissue equivalent phantoms following the introduction of iodinated contrast media. Methods: The phantom consisted of a small “contrast sphere,” filled with water or iodinated contrast, located at the center of a 28 cm diameter water sphere. Monte Carlo simulations were performed using MCNP5 codes, validated by simulating irradiations with analytical solutions. Monoenergetic x-rays ranging from 35 to 150 keV were used to simulate exposures to spheres containing contrast agent with iodine concentrations ranging from 1 to 100 mg/ml. Relative values of energy imparted to the contrast sphere, as well as to the whole phantom, were calculated. Changes in patterns of energy deposition around the contrast sphere were also investigated. Results: Small contrast spheres can increase local absorbed dose by a factor of 13, but the corresponding increase in total energy absorbed was negligible (<1%). The highest localized dose increases were found to occur at incident photon energies of about 60 keV. For a concentration of about 10 mg/ml, typical of clinical practice, localized absorbed doses were generally increased by about a factor of two. At this concentration of 10 mg/ml, the maximum increase in total energy deposition in the phantom was only 6%. These simulations demonstrated that increases in contrast sphere doses were offset by corresponding dose reductions at distal and posterior locations. Conclusions: Adding iodine can result in values of localized absorbed dose increasing by more than an order of magnitude, but the total energy deposition is generally very modest (i.e., <10%). Their data show that adding iodine primarily changes the pattern of energy deposition in the irradiated region, rather than increasing patient doses per se.

  12. Dose distribution to spinal structures from intrathecally administered yttrium-90

    NASA Astrophysics Data System (ADS)

    Mardirossian, George; Hall, Michael; Montebello, Joseph; Stevens, Patrick

    2006-01-01

    Previous treatment of cerebrospinal fluid (CSF) malignancies by intrathecal administration of 131I-radiolabelled monoclonal antibodies has led to the assumption that more healthy tissue will be spared when a pure beta-emitter such as 90Y replaces 131I. The purpose of this study is to compare and quantitatively evaluate the dose distribution from 90Y to the CSF space and its surrounding spinal structures to 131I. A 3D digital phantom of a section of the T-spine was constructed from the visible human project series of images which included the spinal cord, central canal, subarachnoid space, pia mater, arachnoid, dura mater, vertebral bone marrow and intervertebral disc. Monte Carlo N-particle (MCNP4C) was used to model the 90Y and 131I radiation distribution. Images of the CSF compartment were convolved with the radiation distribution to determine the dose within the subarachnoid space and surrounding tissues. 90Y appears to be a suitable radionuclide in the treatment of central nervous system (CNS) malignancies when attached to mAb's and the dose distribution would be confined largely within the vertebral foramen. This choice may offer favourable dose improvement to the subarachnoid and surface of spinal cord over 131I in such an application.

  13. Orally administered betaine has an acute and dose-dependent effect on serum betaine and plasma homocysteine concentrations in healthy humans.

    PubMed

    Schwab, Ursula; Törrönen, Anneli; Meririnne, Esa; Saarinen, Markku; Alfthan, Georg; Aro, Antti; Uusitupa, Matti

    2006-01-01

    Betaine, i.e., trimethylglycine, is linked to homocysteine metabolism. A 3-mo daily betaine supplementation decreased even normal plasma total homocysteine (tHcy) concentrations in humans. The pharmacokinetic characteristics and metabolism of betaine in humans have not been investigated in detail. The aim of this study was to assess the pharmacokinetics of orally administered betaine and its acute effect on plasma tHcy concentrations. Healthy volunteers (n = 10; 3 men, 7 women) with normal body weight (mean +/- SD, 69.5 +/- 17.0 kg), 40.8 +/- 12.4 y old, participated in the study. The betaine doses were 1, 3, and 6 g. The doses were mixed with 150 mL of orange juice and ingested after a 12-h overnight fast by each volunteer according to a randomized double-blind crossover design. Blood samples were drawn for 24 h and a 24-h urine collection was performed. Orally administered betaine had an immediate and dose-dependent effect on serum betaine concentration. Single doses of 3 and 6 g lowered plasma tHcy concentrations (P = 0.019 and P < 0.001, respectively), unlike the 1-g dose. After the highest dose, the concentrations remained low during the 24 h of monitoring. The change in plasma tHcy concentration was linearly associated with betaine dose (P = 0.006) and serum betaine concentration (R2 = 0.17, P = 0.025). The absorption and elimination of betaine were dose dependent. The urinary excretion of betaine seemed to increase with an increasing betaine dose, although a very small proportion of ingested betaine was excreted via urine. In conclusion, a single dose of orally administered betaine had an acute and dose-dependent effect on serum betaine concentration and resulted in lowered plasma tHcy concentrations within 2 h in healthy subjects. PMID:16365055

  14. Dose Dependence of the Anticoagulant Effect of Intravenously Administered Cellulose Sulfate.

    PubMed

    Drozd, N N; Kuznetsova, S A; Kalinina, T B; Vasilieva, N Yu

    2016-04-01

    Experiments on rabbits showed that increasing the dose of intravenously administered cellulose sulfate from wheat straw (dynamic viscosity 3.4 cP, sulfur content 14.1%) increased plasma clotting time in some coagulation tests and plasma anticoagulant activity. When cellulose sulfate was administered in the dose of 1 mg/kg, plasma clotting time in the presence of the anticoagulant (5 min after administration) was ~3-fold higher than after saline administration. PMID:27165079

  15. Vitamin C modulates lead excretion in rats

    PubMed Central

    Lihm, Hoseob; Kim, Hyun; Chang, Heekyung; Yoon, Myunghee; Lee, Kayoung

    2013-01-01

    Lead, one of the most toxic heavy metals, takes longer time to be excreted from the body than other heavy metals. The purpose of this study is, by measuring lead excretion via urine and feces, to find out the effect of vitamin C in lead chelation. Thirty-six rats were randomly assorted into four groups. All 33 rats except for the control group were administered with lead, before orally administered with different doses of vitamin C per kilogram of body weight. The lead excretion levels in urine and feces as well as the survival rate were then measured for each group. The rats with lead administrations (10/13, 76.9%) with lead administrations only, 10/11 rats (90.9%) with lead administrations and low dose of vitamin C, 9/9 rats (100%) with lead administrations and high dose of vitamin C survived. Among the 29 surviving rats, low vitamin C intake group exhibited higher urinary excretion than the lead only group. The urinary excretion level in high dose vitamin C intakegroup was significantly higher than the lead only group. In addition, fecal lead excretion seemed to be increased in the high dose vitamin C intake group, compared to the group with lead administrations only with statistical significance. Through animal experiment, it was found out that administrating high dose of vitamin C accelerated the excretion of lead in body compared to low dose of vitamin C. PMID:24386596

  16. Human metabolism and excretion kinetics of aniline after a single oral dose.

    PubMed

    Modick, Hendrik; Weiss, Tobias; Dierkes, Georg; Koslitz, Stephan; Käfferlein, Heiko Udo; Brüning, Thomas; Koch, Holger Martin

    2016-06-01

    Aniline is an important source material in the chemical industry (e.g., rubber, pesticides, and pharmaceuticals). The general population is known to be ubiquitously exposed to aniline. Thus, assessment of aniline exposure is of both occupational and environmental relevance. Knowledge on human metabolism of aniline is scarce. We orally dosed four healthy male volunteers (two fast and two slow acetylators) with 5 mg isotope-labeled aniline, consecutively collected all urine samples over a period of 2 days, and investigated the renal excretion of aniline and its metabolites by LS-MS/MS and GC-MS. After enzymatic hydrolysis of glucuronide and sulfate conjugates, N-acetyl-4-aminophenol was the predominant urinary aniline metabolite representing 55.7-68.9 % of the oral dose, followed by the mercapturic acid conjugate of N-acetyl-4-aminophenol accounting for 2.5-6.1 %. Acetanilide and free aniline were found only in minor amounts accounting for 0.14-0.36 % of the dose. Overall, these four biomarkers excreted in urine over 48 h post-dose represented 62.4-72.1 % of the oral aniline dose. Elimination half-times were 3.4-4.3 h for N-acetyl-4-aminophenol, 4.1-5.5 h for the mercapturic acid conjugate, and 1.3-1.6 and 0.6-1.2 h for acetanilide and free aniline, respectively. Urinary maximum concentrations of N-acetyl-4-aminophenol were reached after about 4 h and maximum concentrations of the mercapturic acid conjugate after about 6 h, whereas concentrations of acetanilide and free aniline peaked after about 1 h. The present study is one of the first to provide reliable urinary excretion factors for aniline and its metabolites in humans after oral dosage, including data on the predominant urinary metabolite N-acetyl-4-aminophenol, also known as an analgesic under the name paracetamol/acetaminophen. PMID:26233686

  17. First results on the incorporation and excretion of 15N from orally administered urea in lactating pony mares.

    PubMed

    Schubert, R; Zander, R; Gruhn, K; Hennig, A

    1991-05-01

    Two lactating pony mares were given oral offers of 20 g 15N urea [95 atom-% 15N-excess (15N')] on 6 subsequent days. About 80% of the consumed 15N' were excreted via urine and faeces, but only about 2% via milk. The 15N' secreted via milk-lysine only amounted to 0.04% of the 15N' intake. The recovery was about 90% in each case. Tissues with active metabolism had an unexpectedly high labelling (greater than 0.3 atom-% 15N'). The low extent of the conversion of oral urea N into milk-lysine speaks against an essential participation of the enteral synthesis in meeting the amino acid requirement of lactating mares. It was already concluded from this results that the determination of the amino acid requirement will be necessary for this group of performance. PMID:1888274

  18. Prescription opioids. II. Metabolism and excretion patterns of hydrocodone in urine following controlled single-dose administration.

    PubMed

    Cone, Edward J; Heltsley, Rebecca; Black, David L; Mitchell, John M; Lodico, Charles P; Flegel, Ronald R

    2013-10-01

    Hydrocodone (HC) is a highly misused prescription drugs in the USA. Interpretation of urine tests for HC is complicated by its metabolism to two metabolites, hydromorphone (HM) and dihydrocodeine (DHC), which are also available commercially and are misused. Currently, there is interest in including HC and HM in the federal workplace drug-testing programs. This study characterized the disposition of HC in human urine. Twelve healthy, drug-free, adults were administered a single, oral 20 mg immediate-release dose of HC in a controlled clinical setting. Urine specimens were collected at timed intervals for up to 52 h and analyzed by LC-MS-MS (limit of quantitation = 50 ng/mL) with and without enzymatic hydrolysis. All specimens were also analyzed for creatinine and specific gravity (SG). HC and norhydrocodone (NHC) appeared within 2 h followed by HM and DHC. Peak concentrations of HC and metabolites occurred at 3-9 h. Peak hydrolyzed concentrations were in the order: NHC > HC > HM > DHC. Only HM was excreted extensively as a conjugated metabolite. At a cutoff concentration of 50 ng/mL, detection times were ∼28 h for HC, 40 h for NHC, 26 h for HM and 16 h for DHC. Some specimens did not contain HC, but most contained NHC, thereby facilitating interpretation that HC was the administered drug. Creatinine and SG measures were highly correlated. Creatinine corrections of HC urinary data had variable effects of lowering or raising concentrations. These data suggest that drug-testing requirements for HC should include a hydrolysis step and a test for HM. PMID:23946451

  19. Subpressor doses of angiotensin II do not increase albumin excretion in humans.

    PubMed

    Erley, C M; Grau, C; Furian, T C; Wolf, S; Braun, N; Risler, T

    1996-11-01

    The objective of our study was to evaluate the effects of subpressor doses of angiotensin II and mild physical stress on renal hemodynamics and urinary albumin excretion (UAE) in a group of young patients with essential hypertension compared to normotensive subjects. Eleven patients (26 +/- 6 years) and ten healthy control persons (25 +/- 2 years) were enrolled in the study. Secondary forms of hypertension had been excluded. Angiotensin II was infused at a dose of 0.3 and 1.0 ng/kg/min and physical stress testing was done with a cycle ergometer (50 W at 10 min for hypertensives, 100 W at 10 min for normotensives). Renal hemodynamics were assessed by clearance techniques (continuous insulin and p-aminohippurate clearance). Mean arterial pressure (MAP) and UAE were significantly higher in the hypertensive group than in normotensive control persons at any time of measurement. There was no significant increase in MAP or UAE under angiotensin II infusion either in the hypertensive group or in the normotensive group. MAP increased significantly under physical stress in the normotensive group only (83 +/- 7 mmHg baseline vs. 108 +/- mmHg during physical stress, p < 0.05). Angiotensin II infusion resulted in a significant change concerning renal hemodynamics in the hypertensive group only. The filtration fraction increased (18 +/- 3% baseline vs. 25 +/- 7% under infusion of 1.0 ng/kg/min angiotensin II, p < 0.05) due to a decline in ERPF and an increase in GFR in the hypertensive group. The amount of UAE correlated with the magnitude of the MAP in both groups. No correlation was found between renal hemodynamic parameters and the UAE. A significant correlation was found between the norepinephrine levels and the UAE in the control group. We could not demonstrate an albuminuric effect of subpressor doses of angiotensin II in normotensive or hypertensive subjects despite its well known effects on renal hemodynamics with an increase of the filtration fraction. These data

  20. Absorption, Distribution, and Excretion of the Investigational Agent Orteronel (TAK-700) in Healthy Male Subjects: A Phase 1, Open-Label, Single-Dose Study.

    PubMed

    Suri, Ajit; Pusalkar, Sandeepraj; Li, Yuexian; Prakash, Shimoga

    2016-05-01

    This study evaluated the absorption, distribution, and excretion of orteronel, an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. Six healthy male subjects received a single 400-mg dose of radiolabeled [(14) C]-orteronel (18.5 kBq). The pharmacokinetics of [(14) C]-radioactivity, orteronel, and the primary metabolite M-I were characterized by ultra-performance liquid chromatography-tandem mass spectrometry, and mass balance recovery of [(14) C]-radioactivity was determined by liquid scintillation counting and accelerator mass spectrometry. Median time to maximum observed concentration of [(14) C]-radioactivity was 2.5 hours (plasma/whole blood) and of orteronel was 1 hour (plasma). Mean terminal half-life for [(14) C]-radioactivity in plasma and whole blood was 9.46 and 7.39 hours, respectively. For [(14) C]-radioactivity, the geometric mean whole blood-to-plasma ratios for maximum observed plasma/whole-blood concentration, area under the plasma concentration-time curve from time 0 to last quantifiable concentration (AUC0-last ), and AUC0-inf (AUC from time 0 to infinity) were 1.04, 0.92, and 0.93, respectively. Dose recovery accounted for 95.9% of the administered orteronel dose; the majority of excretion occurred by 96 hours postdose. The principal excretion route was via urine (mean, 77.5%; including 49.7% unchanged drug and 16.3% M-I) compared with 18.4% via feces. Three mild adverse events were reported; none were considered serious or related to orteronel. PMID:27163496

  1. Effects of methylxanthines on urinary prostaglandin E excretion in rats.

    PubMed

    Takeuchi, K; Kogo, H; Aizawa, Y

    1981-04-01

    Effect of methylxanthines (theophylline, theobromine and caffeine) on urinary prostaglandin E (PGE) excretion in male rats was studied. Oral administration of xanthines significantly increased the urinary excretion of PGE. Dose-response studies showed that the maximal excretion of urinary PGE and water was obtained by administration of theophylline (50 mg/kg), where the increase in PGE was about 20 times that of the control. The excretion of urinary sodium, potassium and chloride was also markedly increased by xanthines, particularly, theophylline. Increases in urinary PGE excretion, urine volume and electrolytes excretion were inhibited by 10 mg/kg of indomethacin administered prior to theophylline. The increase of urinary PGE excretion after theophylline administration (50 mg/kg) preceded increases in water and sodium excretion. These results suggest that renal PGE mediates, at least in part, the diuretic effect of theophylline. PMID:7311144

  2. Dose and elasticity of demand for self-administered cocaine in rats.

    PubMed

    Kearns, David N; Silberberg, Alan

    2016-04-01

    The present experiment tested whether the elasticity of demand for self-administered cocaine in rats is dose-dependent. Subjects lever pressed for three different doses of intravenous cocaine - 0.11, 0.33, and 1.0 mg/kg/infusion - on a demand procedure where the number of lever presses required per infusion increased within a session. The main finding was that demand for the 0.11 mg/kg dose was more elastic than it was for the two larger doses. There was no difference in demand elasticity between the 0.33 and 1.0 mg/kg doses. These results parallel findings previously reported in monkeys. The present study also demonstrated that a within-session procedure can be used to generate reliable demand curves. PMID:26866971

  3. Brachytherapy Application with in situ Dose-painting Administered via Gold-nanoparticle Eluters

    PubMed Central

    Sinha, Neeharika; Cifter, Gizem; Sajo, Erno; Kumar, Rajiv; Sridhar, Srinivas; Nguyen, Paul; Cormack, Robert A; Makrigiorgos, G. Mike; Ngwa, Wilfred

    2014-01-01

    Purpose Recent studies show promise that administering gold nanoparticles (GNP) to tumor cells during brachytherapy could significantly enhance radiation damage to the tumor. A proposed new strategy for sustained administration of the GNP in prostate tumors is to load them into routinely used brachytherapy spacers for customizable in-situ release after implantation. This in silico study investigates the intra-tumor biodistribution and corresponding dose enhancement over time due to GNP released from such GNP-loaded brachytherapy spacers (GBS). Method and Materials An experimentally determined intra-tumoral diffusion coefficient (D) for 10 nm nanoparticles was employed to estimate D for other sizes using the Stoke-Einstein equation. GNP concentration profiles, obtained using D, were then employed to calculate the corresponding dose enhancement factor (DEF) for each tumor voxel using dose-painting by numbers approach, for times relevant to the considered brachytherapy sources' lifetimes. The investigation is carried out as a function of GNP size for clinically applicable low dose rate brachytherapy sources: I-125, Pd-103, Cs-131. Results Results showed that dose enhancement to tumor voxels/sub-volumes during brachytherapy can be customized by varying the sizes of GNP released or eluted from the GBS. For example, using 7 mg/g GNP concentration, significant DEF (> 20%) could be achieved 5 mm from a GBS after 5, 12, 25, 46, 72, 120, and 195 days, respectively, for GNPs sizes of 2 nm, 5 nm, 10 nm, 20 nm, 30 nm 50 nm, and 80 nm when treating with I-125. Conclusions Analyses show that using Cs-131 provides the highest dose enhancement to tumor voxels. However, given its relatively longer half-life, I-125 presents the most flexibility for customizing the dose enhancement as a function of GNP size. The findings provide a useful reference for further work towards potential development of a new brachytherapy application with in-situ dose-painting administered via gold

  4. PHARMACOKINETICS OF SINGLE-DOSE ORALLY ADMINISTERED CIPROFLOXACIN IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS).

    PubMed

    Barbosa, Lorraine; Johnson, Shawn P; Papich, Mark G; Gulland, Frances

    2015-06-01

    Ciprofloxacin is commonly selected for clinical use due to its broad-spectrum efficacy and is a frequently administered antibiotic at The Marine Mammal Center, a marine mammal rehabilitation facility. Ciprofloxacin is used for treatment of California sea lions ( Zalophus californianus ) suffering from a variety of bacterial infections at doses extrapolated from other mammalian species. However, as oral absorption is variable both within and across species, a more accurate determination of appropriate dosage is needed to ensure effective treatment and avoid emergence of drug-resistant bacterial strains. A pharmacokinetic study was performed to assess plasma concentrations of ciprofloxacin in California sea lions after a single oral dose. Twenty healthy California sea lions received a single 10-mg/kg oral dose of ciprofloxacin administered in a herring fish. Blood was then collected at two of the following times from each individual: 0.5, 0.75, 1, 2, 4, 8, 10, 12, 18, and 24 hr postingestion. Plasma ciprofloxacin concentration was assessed via high-performance liquid chromatography. A population pharmacokinetics model demonstrated that an oral ciprofloxacin dose of 10 mg/kg achieved an area under the concentration vs. time curve of 6.01 μg hr/ml. Absorption was rapid, with ciprofloxacin detectable in plasma 0.54 hr after drug administration; absorption half-life was 0.09 hr. A maximum plasma concentration of 1.21 μg/ml was observed at 1.01 hr, with an elimination half-life of 3.09 hr. Ciprofloxacin administered orally at 10 mg/kg produced therapeutic antibacterial exposure for only some of the most susceptible bacterial organisms commonly isolated from California sea lions. PMID:26056878

  5. Brachytherapy Application With In Situ Dose Painting Administered by Gold Nanoparticle Eluters

    SciTech Connect

    Sinha, Neeharika; Cifter, Gizem; Sajo, Erno; Kumar, Rajiv; Sridhar, Srinivas; Nguyen, Paul L.; Cormack, Robert A.; Makrigiorgos, G. Mike; Ngwa, Wilfred

    2015-02-01

    Purpose: Recent studies show promise that administering gold nanoparticles (GNP) to tumor cells during brachytherapy could significantly enhance radiation damage to the tumor. A new strategy proposed for sustained administration of the GNP in prostate tumors is to load them into routinely used brachytherapy spacers for customizable in situ release after implantation. This in silico study investigated the intratumor biodistribution and corresponding dose enhancement over time due to GNP released from such GNP-loaded brachytherapy spacers (GBS). Method and Materials: An experimentally determined intratumoral diffusion coefficient (D) for 10-nm nanoparticles was used to estimate D for other sizes by using the Stokes-Einstein equation. GNP concentration profiles, obtained using D, were then used to calculate the corresponding dose enhancement factor (DEF) for each tumor voxel, using dose painting-by-numbers approach, for times relevant to the considered brachytherapy sources' lifetimes. The investigation was carried out as a function of GNP size for the clinically applicable low-dose-rate brachytherapy sources iodine-125 (I-125), palladium-103 (Pd-103), and cesium-131 (Cs-131). Results: Results showed that dose enhancement to tumor voxels and subvolumes during brachytherapy can be customized by varying the size of GNP released or eluted from the GBS. For example, using a concentration of 7 mg/g GNP, significant DEF (>20%) could be achieved 5 mm from a GBS after 5, 12, 25, 46, 72, 120, and 195 days, respectively, for GNP sizes of 2, 5, 10, 20, 30, and 50 nm and for 80 nm when treating with I-125. Conclusions: Analyses showed that using Cs-131 provides the highest dose enhancement to tumor voxels. However, given its relatively longer half-life, I-125 presents the most flexibility for customizing the dose enhancement as a function of GNP size. These findings provide a useful reference for further work toward development of potential new brachytherapy application with

  6. The safety of high-dose buprenorphine administered subcutaneously in cats.

    PubMed

    Sramek, M K; Haas, M C; Coleman, G D; Atterson, P R; Hamlin, R L

    2015-10-01

    The safety of a proprietary formulation of buprenorphine hydrochloride administered subcutaneously (SC) to young cats was investigated in a blinded, randomized study. Four cohorts of eight cats aged approximately 4 months were administered saline, 0.24, 0.72 or 1.20 mg/kg/day buprenorphine SC for nine consecutive days, representing 0×, 1×, 3× and 5× of the intended dose. Cats were monitored daily for evidence of clinical reactions, food and water intake and adverse events (AEs). Physical examinations, clinical pathology, vital signs and electrocardiograms (ECGs) were evaluated at protocol-specified time points. Complete necropsy and histopathologic examinations were performed following humane euthanasia. Four buprenorphine-treated cats experienced AEs during the study, two unrelated and two related to study drug administration. The two cats with AEs considered related to drug administration had clinical signs of hyperactivity, difficulty in handling, disorientation, agitation and dilated pupils in one 0.24 mg/kg/day cat and one 0.72 mg/kg/day cat. All of these clinical signs were observed simultaneously. There were no drug-related effects on survival, injection response, injection site inspections, body weight, food or water consumption, bleeding time, urinalysis, respiration rate, heart rate, ECGs, blood pressures, body temperatures, macroscopic examinations or organ weights. Once daily buprenorphine s.c. injections at doses of 0.24, 0.72 and 1.20 mg/kg/day for 9 consecutive days were well tolerated in young domestic cats. PMID:25623082

  7. Dose-response toxicity studies on tributoxyethyl phosphate orally administered to Sprague-Dawley rats

    SciTech Connect

    Laham, S.; Szabo, J.; Long, G.; Schrader, K.

    1985-08-01

    The response of the peripheral nervous system to various dose levels of tributoxyethyl phosphate (TBOP) was investigated in Sprague-Dawley rats. Groups of randomized female and male rats (10 rats/gender/dose level) were administered a single oral dose of TBOP (1.0 to 3.2 g/kg for females;1.0 to 9.0 g/kg for males). Physiological parameters were measured in surviving rats three weeks following TBOP administration. A significant reduction (p<0.05) in caudal nerve conduction velocity (NCV) was observed in both female and male rats. Light and electron microscopic examination of sciatic nerve sections showed degenerative changes in both myelinated and unmyelinated fibers of female (2.0 g/kg) and male (6.8 g/kg) groups. Advanced degeneration was observed only in the highest dose level of both genders (3.2 g/kg for females; 8.0 and 9.0 g/kg for males). Although similar morphological changes were observed in both genders, females were more susceptible than males to the toxic effects of this compound.

  8. Radiosensitizing activity and pharmacokinetics of multiple dose administered KU-2285 in peripheral nerve tissue in mice

    SciTech Connect

    Iwai, Hiroyuki; Matsuno, Etsuko ); Sasai, Keisuke; Abe, Mitsuyuki; Shibamoto, Yuta )

    1994-06-15

    In a clinical trial in which a 2-nitroimidazole radiosensitizer was administered repeatedly, the dose-limiting toxicity was found to be peripheral neuropathy. In the present study, the in vivo radiosensitizing activity of KU-2285 in combination with radiation dose fractionation, and the pharmacokinetics of cumulative dosing of KU-2285 in the peripheral nerves were examined. The ability of three nitroimidazoles, misonidazole (MISO), etanidazole (SR-2508) and KU-2285, to sensitize SCCVII tumors to radiation treatment has been compared for drug doses in the range 0-200 mg/kg. Single radiation doses or two different fractionation schedules (6 Gy/fractions [times] three fractions/48 h or 5 Gy/fractions [times] five fractions/48 h) were used; the tumor cell survival was determined using an in vivo/in vitro colony assay. The pharmacokinetics in the sciatic nerves were undertaken, when KU-2285 or etanidazole were injected at a dose of 200 mg/kg intravenously one, two, three, or four times at 2-h intervals. At less than 100 mg/kg, KU-2285 sensitized SCCVII tumors more than MISO and SR-2508 by fractionated irradiation. Evaluation of pharmacokinetics in the peripheral nerves showed that the apparent biological half-life of SR-2508 increased with the increases in the number of administrations, whereas that of KU-2285 became shorter. Since most clinical radiotherapy is given in small multiple fractions, KU-2285 appears to be a hypoxic cell radiosensitizer that could be useful in such regimens, and that poses no risk of chronic peripheral neurotoxicity. 12 refs., 5 figs., 1 tab.

  9. Measured dose rate constant from oncology patients administered 18F for positron emission tomography

    SciTech Connect

    Quinn, Brian; Holahan, Brian; Aime, Jean; Humm, John; St Germain, Jean; Dauer, Lawrence T.

    2012-10-15

    Purpose: Patient exposure rate measurements verify published patient dose rate data and characterize dose rates near 2-18-fluorodeoxyglucose ({sup 18}F-FDG) patients. A specific dose rate constant based on patient exposure rate measurements is a convenient quantity that can be applied to the desired distance, injection activity, and time postinjection to obtain an accurate calculation of cumulative external radiation dose. This study reports exposure rates measured at various locations near positron emission tomography (PET) {sup 18}F-FDG patients prior to PET scanning. These measurements are normalized for the amount of administered activity, measurement distance, and time postinjection and are compared with other published data. Methods: Exposure rates were measured using a calibrated ionization chamber at various body locations from 152 adult oncology patients postvoid after a mean uptake time of 76 min following injection with a mean activity of 490 MBq {sup 18}F-FDG. Data were obtained at nine measurement locations for each patient: three near the head, four near the chest, and two near the feet. Results: On contact with, 30 cm superior to and 30 cm lateral to the head, the mean (75th percentile) dose rates per unit injected activity at 60 min postinjection were 0.482 (0.511), 0.135 (0.155), and 0.193 (0.223) {mu}Sv/MBq h, respectively. On contact with, 30 cm anterior to, 30 cm lateral to and 1 m anterior to the chest, the mean (75th percentile) dose rates per unit injected activity at 60 min postinjection were 0.623 (0.709), 0.254 (0.283), 0.190 (0.218), and 0.067 (0.081) {mu}Sv/MBq h respectively. 30 cm inferior and 30 cm lateral to the feet, the mean (75th percentile) dose rates per unit injected activity at 60 min postinjection were 0.024 (0.022) and 0.039 (0.044) {mu}Sv/MBq h, respectively. Conclusions: The measurements for this study support the use of 0.092 {mu}Sv m{sup 2}/MBq h as a reasonable representation of the dose rate anterior from the chest of

  10. Alternative low doses and routes of administering a prostaglandin F2α analogue to induce luteolysis in Nelore cows

    PubMed Central

    Pessoa, Valsair Matos; Ferreira, João Carlos Pinheiro; Araujo, Gustavo Henrique M.; Gioso, Marilu M.; Bicudo, Sony Dimas; Oba, Eunice; Orlandi, Cassia

    2006-01-01

    The present study was conducted in order to verify the efficacy of lower doses and alternative routes of a prostaglandin F2α analogue, luprostiol (PGF), for the induction of luteolysis and the precipitation of estrus in nonlactating Nelore cows (Bos taurus indicus). A conventional dose (15 mg) of PGF was compared to doses lower than the conventional dose, which ranges from 10 to 50%, that were administered intramuscularly (IM), intravulvosubmucosally (IVSM), or in the Bai-hui acupuncture site located within the lumbosacral area. The cows were administered PGF 8 day after estrus in the presence of a corpus luteum, and randomly assigned to the following groups: G1 (positive control), 15 mg, IM (n = 23); G2, 7.5 mg, IM (n = 23); G3, 3.75 mg, IM (n = 24); G4, 7.5 mg, IVSM (n = 25); G5, 3.75 mg, Bai-hui acupoint (n = 24); and G6, 1.5 mg, Bai-hui acupoint (n = 25). The results indicated that 50% of a conventional dose of PGF (7.5 mg) resulted in a complete luteal regression (plasma progesterone <1 ng/ml) at Hour 48, and hastened estrus, regardless of whether or not PGF was administered IM or IVSM. Comparatively, 10 or 25% of the conventional dose, even when administered to the Bai-hui acupoint, resulted in an initial reduction in the concentration of progesterone at Hour 24, followed by an increase observed at Hour 48. In conclusion, 25% of a conventional PGF dose administered via the Bai-hui acupoint proved inadequate to induce a complete luteal regression, whereas 50% of a conventional dose administered IM or IVSM was found to be the minimal dose required to induce effectively a complete luteal regression, and to precipitate the onset of estrus in nonlactating Nelore cows. PMID:17106232

  11. Excretion profile of hydrocodone, hydromorphone and norhydrocodone in urine following single dose administration of hydrocodone to healthy volunteers.

    PubMed

    Valtier, Sandra; Bebarta, Vikhyat S

    2012-09-01

    Abuse of prescription opioids for non-medical use has been on the rise over the past decade. The most commonly abused opioid is hydrocodone, a frequently prescribed pain medication metabolized by the body to hydromorphone, norhydrocodone and other minor metabolites. This study describes the excretion profile of hydrocodone, hydromorphone and norhydrocodone in urine following a single dose (10 mg) administration of hydrocodone to human subjects (n = 7) and presents a validated liquid chromatography-tandem mass spectrometry method for analysis of the drug and its metabolites. Limit of quantitation was 5 ng/mL for all analytes; limit of detection was 2.5 ng/mL for hydrocodone and norhydrocodone and 5 ng/mL for hydromorphone. Peak concentrations of hydrocodone were found at 3:30-7:00 hours post-dose and were in the range of 612-2,190 ng/mL. Hydromorphone peak concentrations were found at 6:15-26:45 hours post-dose and ranged from 102 to 342 ng/mL. For norhydrocodone, peak concentrations were found at 4:20-13:00 hours post-dose and ranged from 811 to 3,460 ng/mL. Although hydromorphone was found at lower levels than hydrocodone, in six of seven subjects, it persisted for as long as hydrocodone was detected. Norhydrocodone was found at higher levels and lasted for a longer period of time than hydrocodone, thus making the nor-metabolite a valuable tool in evaluating hydrocodone use and/or misuse. PMID:22782534

  12. Excretion of Antibiotic Resistance Genes by Dairy Calves Fed Milk Replacers with Varying Doses of Antibiotics

    PubMed Central

    Thames, Callie H.; Pruden, Amy; James, Robert E.; Ray, Partha P.; Knowlton, Katharine F.

    2012-01-01

    Elevated levels of antibiotic resistance genes (ARGs) in soil and water have been linked to livestock farms and in some cases feed antibiotics may select for antibiotic resistant gut microbiota. The purpose of this study was to examine the establishment of ARGs in the feces of calves receiving milk replacer containing no antibiotics versus subtherapeutic or therapeutic doses of tetracycline and neomycin. The effect of antibiotics on calf health was also of interest. Twenty-eight male and female dairy calves were assigned to one of the three antibiotic treatment groups at birth and fecal samples were collected at weeks 6, 7 (prior to weaning), and 12 (5 weeks after weaning). ARGs corresponding to the tetracycline (tetC, tetG, tetO, tetW, and tetX), macrolide (ermB, ermF), and sulfonamide (sul1, sul2) classes of antibiotics along with the class I integron gene, intI1, were monitored by quantitative polymerase chain reaction as potential indicators of direct selection, co-selection, or horizontal gene transfer of ARGs. Surprisingly, there was no significant effect of antibiotic treatment on the absolute abundance (gene copies per gram wet manure) of any of the ARGs except ermF, which was lower in the antibiotic-treated calf manure, presumably because a significant portion of host bacterial cells carrying ermF were not resistant to tetracycline or neomycin. However, relative abundance (gene copies normalized to 16S rRNA genes) of tetO was higher in calves fed the highest dose of antibiotic than in the other treatments. All genes, except tetC and intI1, were detectable in feces from 6 weeks onward, and tetW and tetG significantly increased (P < 0.10), even in control calves. Overall, the results provide new insight into the colonization of calf gut flora with ARGs in the early weeks. Although feed antibiotics exerted little effect on the ARGs monitored in this study, the fact that they also provided no health benefit suggests that the greater than conventional

  13. Bronchodilator effect of single-dose formoterol administered by pressurized metered-dose inhaler in children with asthma aged 6 to <12 years receiving budesonide.

    PubMed

    Berger, William E; Gillen, Michael; Eckerwall, Göran; Uryniak, Tom; Trudo, Frank J; Lampl, Kathy L

    2014-01-01

    Dose-response of formoterol via pressurized metered-dose inhaler (pMDI) has not been determined in asthmatic pediatric patients aged 6 to <12 years. This study was designed to assess the bronchodilating dose-response of three formoterol pMDI doses in children with stable asthma aged 6 to <12 years receiving twice-daily (b.i.d.) budesonide 160 micrograms. A U.S., multicenter, five-way crossover study compared single doses of formoterol, a long-acting beta-agonist, via pMDI (2.25, 4.5, and 9 micrograms) or dry powder inhaler (12 micrograms; active comparator) and placebo, with a 3- to 14-day washout period between doses. Budesonide pMDI 160 micrograms, an inhaled corticosteroid, was given b.i.d. throughout the study. Fifty-four pediatric patients (mean age, 9.2 years; mean asthma history, 6.1 years) were randomized. All formoterol doses showed significantly higher average 12-hour forced expiratory volume in 1 second (FEV1; area under the curve) versus placebo (primary efficacy). Formoterol pMDI 4.5 and 9 micrograms showed significantly greater average 12-hour FEV1 than formoterol 2.25 micrograms (p = 0.0007 and p = 0.0001, respectively). Formoterol also resulted in significant improvement in maximum FEV1 during the 12-hour treatment period (secondary efficacy) with formoterol 4.5-, 9-, and 12-microgram doses versus placebo and the formoterol 2.25-microgram dose. Bronchodilation was not maintained during the 12-hour dosing interval with formoterol 2.25 micrograms. No serious adverse events were reported. Formoterol pMDI showed generally dose-proportional pharmacokinetics to 9 micrograms, as determined by urinary excretion. Single doses of formoterol pMDI showed a dose-response, with formoterol 9 micrograms exhibiting a maximum response, in pediatric patients aged 6 to <12 years with persistent stable asthma maintained on b.i.d. budesonide pMDI 160 micrograms. Clinical trial NCT01136655, www.clinicaltrials.gov. PMID:24717790

  14. Safety and pharmacokinetics of multiple doses of aclidinium bromide administered twice daily in healthy volunteers.

    PubMed

    Lasseter, K; Dilzer, S; Jansat, J M; Garcia Gil, E; Caracta, C F; Ortiz, S

    2012-04-01

    Chronic obstructive pulmonary disease (COPD) is characterized by progressive airway obstruction and increased cholinergic tone. The global initiative for chronic obstructive lung disease (GOLD) guidelines recommend long-acting anticholinergics for COPD maintenance treatment. Aclidinium bromide is a novel, long-acting muscarinic antagonist developed for the treatment of COPD. A phase I, randomized, single-blind, multiple-dose clinical trial was conducted to assess the safety and pharmacokinetics (PK) of multiple doses of twice-daily (BID) aclidinium in healthy subjects. Thirty healthy male and female subjects received aclidinium 200 μg, 400 μg, 800 μg, or placebo twice daily for 7 days. Subjects were randomized to 1 of 3 cohorts and 10 subjects in each cohort were randomized (8:2) to either aclidinium or placebo groups. Safety was assessed via adverse events (AEs), laboratory evaluations, vital signs, and ECGs. Plasma samples were obtained at multiple time points throughout the study and analyzed for aclidinium and its inactive acid and alcohol metabolites using a fully validated method of liquid chromatography coupled with tandem mass spectrometry. A total of 9 treatment-emergent AEs were reported (1, placebo; 3, aclidinium 400 μg; 5, aclidinium 800 μg), all of which were mild in severity. No serious AEs were reported. There were no clinically meaningful changes in laboratory parameters or vital signs. PK parameters on Day 7 following BID dosing of aclidinium showed that steady state was achieved for aclidinium and its metabolites. On Days 1 and 7, maximum plasma concentrations (Cmax) of aclidinium were generally observed at the first PK time point (5 min postdose) and rapidly declined, with plasma concentrations generally less than 10% of Cmax by 6 h postdose in all aclidinium groups. Mean effective t(½) after the evening dose on Day 7 ranged from 4.6 to 7.0 h for aclidinium 400 μg and 800 μg, similar to the terminal t(½) observed on Day 1 (4.5-5.9 h

  15. Low-dose cyclophosphamide administered as daily or single dose enhances the antitumor effects of a therapeutic HPV vaccine.

    PubMed

    Peng, Shiwen; Lyford-Pike, Sofia; Akpeng, Belinda; Wu, Annie; Hung, Chien-Fu; Hannaman, Drew; Saunders, John R; Wu, T-C; Pai, Sara I

    2013-01-01

    Although therapeutic HPV vaccines are able to elicit systemic HPV-specific immunity, clinical responses have not always correlated with levels of vaccine-induced CD8(+) T cells in human clinical trials. This observed discrepancy may be attributable to an immunosuppressive tumor microenvironment in which the CD8(+) T cells are recruited. Regulatory T cells (Tregs) are cells that can dampen cytotoxic CD8(+) T-cell function. Cyclophosphamide (CTX) is a systemic chemotherapeutic agent, which can eradicate immune cells, including inhibitory Tregs. The optimal dose and schedule of CTX administration in combination with immunotherapy to eliminate the Treg population without adversely affecting vaccine-induced T-cell responses is unknown. Therefore, we investigated various dosing and administration schedules of CTX in combination with a therapeutic HPV vaccine in a preclinical tumor model. HPV tumor-bearing mice received either a single preconditioning dose or a daily dose of CTX in combination with the pNGVL4a-CRT/E7(detox) DNA vaccine. Both single and daily dosing of CTX in combination with vaccine had a synergistic antitumor effect as compared to monotherapy alone. The potent antitumor responses were attributed to the reduction in Treg frequency and increased infiltration of HPV16 E7-specific CD8(+) T cells, which led to higher ratios of CD8(+)/Treg and CD8(+)/CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs). There was an observed trend toward decreased vaccine-induced CD8(+) T-cell frequency with daily dosing of CTX. We recommend a single, preconditioning dose of CTX prior to vaccination due to its efficacy, ease of administration, and reduced cumulative adverse effect on vaccine-induced T cells. PMID:23011589

  16. Determination of the radiation dose from administered apolipoprotein tracers in humans.

    PubMed

    Venkatakrishnan, V; Fisher, W R; Zech, L A

    1997-10-01

    Radioactive tracers are routinely used in investigation of the metabolism of apolipoprotein kinetics. Here, metabolic studies of apolipoprotein tracers labeled with radioiodine were analyzed to determine the absorbed radiation dose received by the subject. This analysis used compartmental modeling techniques to evaluate the radiation dose to various organs and the total body resulting from radioiodinated tracer injection. In this approach, we combined the published kinetic models of iodine and those of specific apolipoproteins. From the solution of the integrated compartmental models, residence times of the radiation in various source organs, in particular the thyroid, whole body, bladder, and red bone marrow, have been determined for the apolipoproteins apoA-I, apoA-II, very-low-density lipoprotein (VLDL)-apoB, and low-density lipoprotein (LDL)-apoB, each labeled with iodine 123, 133, 124, 131, 126, and 125. These tabulated values were used to calculate radiation doses to the different target organs. The thyroid is the organ that receives the largest dose of delivered radiation, and the importance of the duration of administration of iodine salts in blocking radiation to the thyroid is demonstrated. Optimal block times of 28 days for 131I and 42 days for 125I-labeled apolipoprotein tracers are proposed. When such a protocol is followed, the radiation dose to the thyroid and other organs is small by comparison to radiation doses allowed for workers whose occupation exposes them to radiation. The importance of frequent voiding to reduce the radiation dose to the bladder has also been demonstrated. PMID:9322813

  17. Evaluation of the adverse event profile and pharmacodynamics of toceranib phosphate administered to dogs with solid tumors at doses below the maximum tolerated dose

    PubMed Central

    2013-01-01

    Background The receptor kinase inhibitor toceranib phosphate (Palladia) was approved for use in dogs in 2009 using a dose of 3.25 mg/kg administered every other day. Preliminary data suggests that lower doses of toeceranib may be associated with a reduced adverse event profile while maintaining sufficient drug exposure to provide biologic activity. The purpose of this study was to determine the Cmax of toceranib in dogs with solid tumors receiving 2.5-2.75 mg/kg every other day and to document the adverse events associated with this dose rate. Secondary objectives included determination of plasma VEGF concentrations in treated dogs and response to therapy. Results Dogs with solid tumors were administered toceranib at an intended target dose ranging from 2.5-2.75 mg/kg every other day and plasma samples were obtained for analysis of toceranib and VEGF plasma concentrations on days 0, 7, 14 and 30 of the study at 6 and 8 hours post drug administration. Additionally, plasma samples were obtained at 0, 1, 2, 6, 8, and 12 hours from dogs on day 30 for confirmation of Cmax. Response to therapy was assessed using standard RECIST criteria and adverse events were characterized using the VCOG-CTCAE. Toceranib administered at doses between 2.4-2.9 mg/kg every other day resulted in an average 6–8 hr plasma concentration ranging from 100–120 ng/ml, well above the 40 ng/ml concentration associated with target inhibition. Plasma VEGF concentrations increased significantly over the 30 day treatment period indicating that VEGFR2 inhibition was likely achieved in the majority of dogs. The lower doses of toceranib used in this study were associated with a substantially reduced adverse event profile compared to the established label dose of 3.25 mg/kg EOD. Conclusions Doses of toceranib ranging from 2.4-2.9 mg/kg every other day provide drug exposure considered sufficient for target inhibition while resulting in an adverse event profile substantially reduced from that

  18. [Dose-dependent effects of intracisternally administered insulin on rat's behavior and glucose level].

    PubMed

    Shestakova, S A; Stepanov, I I; Eliseeva, A P; Shatik, S V; Fedorova, N V; Klimenko, V M

    2007-03-01

    Rat behavior in the open field and elevated plus-maze as well as glycaemia level were analyzed in rats after intracisternal administration of 2.5, 25, 50 and 200 ng of insulin. Dose-dependent changes were found in both behavioral tests: insulin in low doses (2.5 and 25 ng) increased probability of locomotion and investigative activity in open field, while insulin in high doses (50 and 200 ng) did not alter locomotor activity and showed tendency to weakening of the investigative behavior (especially in the dose of 50 ng). Significant decrease of rat anxiety level during the first 5 minutes of testing was found after administration of 2.5 and 200 ng of insulin and during the next 5 minutes after administration of 2.5 and 25 ng of insulin in elevated plus-maze. The glucose level in rats was increased in 1-2 hours after insulin administration, though glycaemia level did not exceed normal values. Thus revealed alterations of behavior are supposed to be the result of direct insulin influence on central mechanisms of activation and/or suppression of underlying behavioral characteristics of animals. PMID:17598469

  19. Plasma Epinephrine Levels and Cardiovascular Response to High Administered Doses of Epinephrine in Local Anesthesia

    PubMed Central

    Troullos, Emanuel S.; Goldstein, David S.; Hargreaves, Kenneth M.; Dionne, Raymond A.

    1987-01-01

    The effects of administering an epinephrine-containing local anesthetic on plasma catecholamine levels and cardiovascular parameters were evaluated. Significant elevations were observed following administration of 8 dental cartridges of 2% lidocaine with epinephrine 1:100,000 (144 μg) throughout the 20 minute observation period, while minimal changes were observed in the patients who received 6 cartridges of 3% mepivicaine. One minute after injection, the mean plasma epinephrine level in the group receiving epinephrine was 27.5 times higher than baseline. Concurrent elevations in systolic pressure (15%), heart rate (33%), and the rate-pressure product (52%) were also observed. These results indicate that significant amounts of epinephrine can be systemically absorbed following intraoral injection and the absorbed epinephrine can alter the cardiovascular status of the patient. PMID:3472472

  20. Pharmacokinetics of a low dose and FDA-labeled dose of diclazuril administered orally as a pelleted topdressing in adult horses.

    PubMed

    Hunyadi, L; Papich, M G; Pusterla, N

    2015-06-01

    The purpose of this study was to determine the pharmacokinetics of the FDA-approved labeled dose of diclazuril and compare it to a low dose in plasma and CSF in adult horses. During each research period, six healthy adult horses received 0.5 mg/kg of 1.56% diclazuril pellets (Protazil(TM) , Merck Animal Health) compared to the approved labeled dose of 1 mg/kg orally once in two separate phases. A dose of 0.5 mg/kg was calculated to each horse's weight. Blood was then collected immediately before diclazuril administration and then at regular intervals up to a 168 h. After the last blood collection following the single dose at hour 168, a once daily oral dose was administered for the next 10 days to ensure the drug's concentration reached steady-state. To determine the CSF concentration at steady-state, CSF samples were collected after the 9th oral dose. Blood was then collected after the 10th dose and then at regular intervals up to 168 h. A washout period of 4 weeks was allowed before repeating this protocol for the FDA-labeled dose at 1 mg/kg. Plasma and CSF samples were analyzed by high-pressure liquid chromatography. A one-compartment pharmacokinetic model with first-order oral absorption was fitted to the single administration data. Steady-state pharmacokinetics was performed using noncompartmental analysis for steady-state analysis. The mean (standard deviation) concentration of diclazuril in CSF following the low dose was 26 ng/mL (5 ng/mL), while CSF in the FDA-labeled dose was 25 ng/mL (4 ng/mL), P = 0.3750. Substantial accumulation in plasma occurred at steady-state after the 10th dose for both doses. The results of this study show that diclazuril pellets given at the approved label dose and a lower dose both produce similar plasma drug concentrations at steady-state and attain plasma and CSF concentrations known to inhibit Sarcocystis neurona in cell culture. PMID:25329774

  1. Hypocholesterolaemic effect of rat-administered oral doses of the isolated 7S globulins from cowpeas and adzuki beans.

    PubMed

    Ferreira, Ederlan S; Amaral, Ana Lucia S; Demonte, Aureluce; Zanelli, Cleslei F; Capraro, Jessica; Duranti, Marcello; Neves, Valdir A

    2015-01-01

    The role of seed proteins, especially soyabean 7S globulins, in controlling dyslipidaemia is widely acknowledged. Amino acid sequence homology among the proteins of this family could reflect similar biological functions in other species. The aim of the present study was to unveil a hypolipidaemic effect of the 7S globulins from cowpeas (7S-C) and adzuki beans (7S-A), administered orally to rats fed a hypercholesterolaemic (HC; high cholesterol and TAG) diet for 28 d. A total of forty-five rats were divided into five groups (nine rats per group): (1) standard (STD) diet; (2) HC diet; (3) HC diet + 7S-C (300 mg/kg per d); (4) HC diet + 7S-A (300 mg/kg per d); and (5) HC diet + simvastatin (SVT; 50 mg/kg per d), as a control. Significant decreases in food intake and final body weight of rats receiving HC + 7S-C and HC + 7S-A diets compared with groups fed the HC and STD diets were observed. Significant decreases in serum total and non-HDL-cholesterol of 7S-C, 7S-A and SVT groups were also observed. HDL-cholesterol levels increased in the 7S-C, 7S-A and SVT groups, while hepatic cholesterol and TAG concentrations were significantly lower than in the HC diet group for the 7S-C-supplemented group only. Faecal excretions of fat and cholesterol in HC diet groups were considerably higher in animals consuming the 7S globulins. The results show that cowpea and adzuki bean 7S globulins promote cholesterol-decreasing effects in hypercholesterolaemic rats even at low dosages, as already observed for other legume seed storage proteins of this family. This main effect is discussed in relation to the possible mechanisms of action. PMID:26090103

  2. Use of a hand-held, metered-dose aerosol delivery device to administer pirbuterol acetate to horses with 'heaves'.

    PubMed

    Derksen, F J; Olszewski, M; Robinson, N E; Berney, C; Lloyd, J W; Hakala, J; Matson, C; Ruth, D

    1996-07-01

    Aerosol administration of bronchodilators to horses is recommended for treatment of certain airway diseases such as 'heaves'. We have developed a novel, hand-held, metered-dose inhaler and we sought to determine the bronchodilator efficacy of the beta 2 adrenoceptor agonist pirbuterol delivered by this device to horses affected with 'heaves'. To induce airway obstruction, 6 heaves-susceptible horses were stabled, bedded on straw and fed hay. When the maximum change in pleural pressure during tidal breathing (delta Pplmax) was greater than 20 cmH2O on 2 consecutive days, pulmonary function was measured before and 5, 10 and 30 min, as well as 1, 2, 3, 4, 5, 6 and 7 h after administration of aerosol pirbuterol. Pirbuterol was administered using a metered canister and the hand-held delivery device that was inserted into the left nostril. Either vehicle or pirbuterol acetate (400, 600, 800, 1200 or 1600 micrograms) was administered to each horse. Relief of airway obstruction indicated by changes in pulmonary function was observed within 5 min after administration of both vehicle and pirbuterol. Significant decreases in delta Pplmax and pulmonary resistance (RL) and an increase in dynamic compliance (Cdyn) persisted for the 7 h duration of the experiment. Comparison of the effect of vehicle and pirbuterol at each time period showed that pirbuterol decreased RL and delta Pplmax significantly for up to 1 h. The optimal dose was determined to be 600 micrograms. Immediate response to treatment, magnitude of drug effect and lack of side effects indicated that aerosol pirbuterol is an effective and safe bronchodilator in horses with 'heaves'. The hand-held, metered-dose aerosol delivery device was very convenient and extremely effective and is, therefore, recommended for delivery of therapeutic aerosols to horses. PMID:8818596

  3. HIGH DOSE HYDROXOCOBALAMIN ADMINISTERED AFTER H2S EXPOSURE COUNTERACTS SULFIDE POISONING INDUCED CARDIAC DEPRESSION IN SHEEP

    PubMed Central

    Haouzi, Philippe; Chenuel, Bruno; Sonobe, Takashi

    2015-01-01

    Context Severe H2S poisoning leads to death by rapid respiratory and cardiac arrest, the latter can occur within seconds or minutes in severe forms of intoxication. Objectives Determine the time course and the nature of H2S induced cardiac arrest and the effects of high dose Hydroxocobalamin administered after the end of sulfide exposure. Materials and methods In 16 sedated mechanically ventilated sheep, NaHS was infused to reach concentrations of H2S in the blood we previously found to lead to cardiac arrest within minutes following the cessation of H2S exposure. High dose Hydroxocobalamin (5 g) or saline solution was administered intravenously, one minute after the cessation of NaHS infusion. Results All animals were still alive at the cessation of H2S exposure. Three animals (18%) presented a cardiac arrest within 90 seconds and were unable to receive any antidote or vehicle. In the animals that survived long enough to receive either Hydroxocobalamin or saline, 71% (5/7) died in the control group by cardiac arrest within 10 minutes. In all instances, cardiac arrest was the result of a pulseless electrical activity (PEA). In the group that received the antidote, intravenous injection of 5 g Hydroxocobalamin provoked an abrupt increase in blood pressure and blood flow; PEA was prevented in all instances. However, we could not find any evidence for a recovery in oxidative metabolism in the group receiving Hydroxocobalamin, as blood lactate remained elevated and even continued to rise after one hour, despite restored hemodynamics. This, along with an unaltered recovery of H2S kinetics, suggests that Hydroxocobalamin did not act through a mechanism of H2S trapping. Conclusion In this sheep model, there was a high risk for cardiac arrest, by PEA, persisting up to 10 minutes after H2S exposure. Very high dose of Hydroxocobalamin (5 g), injected very early after the cessation of H2S exposure, improved cardiac contractility and prevented PEA. PMID:25546714

  4. Histopathology of myocardium of copper-deficient rats administered a toxic dose a cocaine

    SciTech Connect

    Burns, W.; Bielenberg, U.; Seung, S.K.; Reddy, P.P.; Dulin, A.M.; Smith, J.C. )

    1989-02-15

    The present study examined the effects of a single dose of cocaine (Coc) on cardiac ultrastructure in rats fed copper sufficient (Cus) compared to copper deficient (CuD) diets. Weanling males were fed either CuS (n-13) or CuD (n-12) for 7 wk. Ten in each group, (paired for Cu status), were injected (ip) with Coc-HCl (80-90mg/kg bw) 5 served as controls. Rats which survived for >15 min, (CuD 40% CuS (80%) controls), were killed and tissues obtained for histology and Cu analysis. Lower Cu concentrations in heart, liver and serum confirmed the CuD. The hearts were examined by light (Lm) and transmission electron microscopy. Myocardial foci showed necrosis, fibrosis, and inflammation in all given Coc but were more severe in the CuD group. CuS controls (no Coc) showed no similar lesions. Ultrastructural observations supported Lm findings. There was an apparent increase in number of mitochondria (Mito) of variable sizes and shapes. Foci of molding Mito and some with crystalline configuration of cristae were also observed. This was most pronounced in the CuD rats given Coc but absent in CuS animals (no Coc). The data support previous findings of myocardial lesionsin CuD rats the effect of Coc in exacerbation these lesions requires further elucidation.

  5. N,N-dimethyl-2-phenylpropan-1-amine quantification in urine: application to excretion study following single oral dietary supplement dose.

    PubMed

    Wójtowicz, Marzena; Jarek, Anna; Chajewska, Katarzyna; Kwiatkowska, Dorota

    2016-07-01

    N,N-dimethyl-2-phenylpropan-1-amine (NN-DMPPA) is a new designer stimulant prohibited in sport in-competition according to the List of Prohibited Substances and Methods published by the World Anti-Doping Agency (WADA). The first published data on the excretion study of NN-DMPPA to support the knowledge of NN-DMPPA in routine anti-doping control have been presented. The reliable gas chromatography-mass spectrometry quantitative method (GC-MS) has been validated and applied to the excretion study of NN-DMPPA. The validation parameters of the GC-MS method for determination of NN-DMPPA in human urine were the linear calibration range of 100 to 7500 ng/mL, the LOD of 13.9 ng/mL and the LOQ of 42.2 ng/mL. According to the obtained repeatability, intermediate precision, and trueness, the applied GC-MS method was precise and accurate. Urine samples from three volunteers in the excretion study were collected for 5 days after single oral administration of the supplement NOXPUMP containing NN-DMPPA. The obtained results showed the maximum concentration of NN-DMPPA (189-303 ng/mL) in urine samples at a time of 2-3 h post-administration. The NN-DMPPA concentration in urine samples was higher than 50 ng/mL until 22-23 h after the dietary supplement ingestion. This means that according to the WADA rules the use of a supplement containing NN-DMPPA may be related to a positive case when athletes took this supplement in-competition. Moreover, excretion results demonstrate also that NN-DMPPA may be detected in urine samples by the applied GC-MS method till 46 h after supplement administration. Additionally, the excretion study of β-methylphenethylamine as the second prohibited substance present in the supplement NOXPUMP has been investigated. Graphical Abstract Excretion study of new designer stimulant, N,N-dimethyl-2-phenylpropan-1-amine, and β-methylphenethylamine following single oral NOXPUMP supplement dose. PMID:27178556

  6. The short- and long-term effects of orally administered high-dose reduced graphene oxide nanosheets on mouse behaviors.

    PubMed

    Zhang, Ding; Zhang, Zheyu; Liu, Yayun; Chu, Maoquan; Yang, Chengyu; Li, Wenhao; Shao, Yuxiang; Yue, Yan; Xu, Rujiao

    2015-11-01

    Reduced graphene oxide (rGO), a carbon-based nanomaterial, has enormous potential in biomedical research, including in vivo cancer therapeutics. Concerns over the toxicity remain outstanding and must be investigated before clinical application. The effect of rGO exposure on animal behaviors, such as learning and memory abilities, has not been clarified. Herein, we explored the short- and long-term effects of orally administered rGO on mouse behaviors, including general locomotor activity level, balance and neuromuscular coordination, exploratory and anxiety behaviors, and learning and memory abilities using open-field, rotarod, and Morris water maze tests. Compared with mice administered buffer-dispersed mouse chow or buffer alone, mice receiving a high dose of small or large rGO nanosheets showed little change in exploratory, anxiety-like, or learning and memory behaviors, although general locomotor activity, balance, and neuromuscular coordination were initially affected, which the mechanisms (e.g. the influence of rGO exposure on the activity of superoxide dismutase in mouse serum) were discussed. The results presented in this work look to provide a deep understanding of the in vivo toxicity of rGO to animals, especially its effect on learning and memory and other behaviors. PMID:26276695

  7. The effect of a booster dose of quadrivalent or bivalent HPV vaccine when administered to girls previously vaccinated with two doses of quadrivalent HPV vaccine.

    PubMed

    Gilca, Vladimir; Sauvageau, Chantal; Boulianne, Nicole; De Serres, Gatson; Crajden, Mel; Ouakki, Manale; Trevisan, Andrea; Dionne, Marc

    2015-01-01

    This randomized, blinded study evaluated the immunogenicity and safety of a booster dose of Gardasil (qHPV) or Cervarix (bHPV) when administered to 12-13 year-old girls who were vaccinated at the age of 9-10 with 2 doses of qHPV (0-6 months). 366 out of 416 eligible girls participated in this follow-up study. Antibody titers were measured just before and one month post-booster. A Luminex Total IgG assay was used for antibody assessment and results are presented in Liminex Units (LU). Three years post-primary vaccination, 99-100% of subjects had detectable antibodies to 4HPV genotypes included in the qHPV with GMTs varying from 50 to 322 LU depending on genotype. After a booster dose of qHPV, a ≥4 fold increase of antibody titers to genotypes included in the vaccine was observed in 88-98% of subjects. Post-booster GMTs varied from 1666 to 4536 LU depending on genotype. These GMTs were 1.1 to 1.8-fold higher when compared to those observed one month post-second dose. After a booster of bHPV, a ≥4 fold increase of antibody titers to HPV16 and HPV18 was observed in 93-99% of subjects. The anti-HPV16 and HPV18 GMTs were 5458 and 2665 LU, respectively. These GMTs were 1.2 and 1.8 higher than those observed in the qHPV group (both P < 0.01). In bHPV group a 1.4-1.6-fold increase of antibody GMTs to HPV6 and HPV11was also observed (P < 0.001). The safety profile was acceptable for both vaccines. Both qHPV and bHPV increase antibody titers when given as a booster to girls previously vaccinated with 2 doses of qHPV. The magnitude of the immune response after booster is vaccine-dependent and has the same pattern as that reported after primary vaccination with qHPV or bHPV. When given as a booster, both vaccines have an acceptable safety profile. Longer follow-up studies are warranted to assess the need of booster doses. PMID:25714044

  8. The effect of a booster dose of quadrivalent or bivalent HPV vaccine when administered to girls previously vaccinated with two doses of quadrivalent HPV vaccine

    PubMed Central

    Gilca, Vladimir; Sauvageau, Chantal; Boulianne, Nicole; De Serres, Gatson; Crajden, Mel; Ouakki, Manale; Trevisan, Andrea; Dionne, Marc

    2015-01-01

    This randomized, blinded study evaluated the immunogenicity and safety of a booster dose of Gardasil (qHPV) or Cervarix (bHPV) when administered to 12–13 year-old girls who were vaccinated at the age of 9–10 with 2 doses of qHPV (0–6 months). 366 out of 416 eligible girls participated in this follow-up study. Antibody titers were measured just before and one month post-booster. A Luminex Total IgG assay was used for antibody assessment and results are presented in Liminex Units (LU). Three years post-primary vaccination, 99–100% of subjects had detectable antibodies to 4HPV genotypes included in the qHPV with GMTs varying from 50 to 322 LU depending on genotype. After a booster dose of qHPV, a ≥4 fold increase of antibody titers to genotypes included in the vaccine was observed in 88–98% of subjects. Post-booster GMTs varied from 1666 to 4536 LU depending on genotype. These GMTs were 1.1 to 1.8-fold higher when compared to those observed one month post-second dose. After a booster of bHPV, a ≥4 fold increase of antibody titers to HPV16 and HPV18 was observed in 93–99% of subjects. The anti-HPV16 and HPV18 GMTs were 5458 and 2665 LU, respectively. These GMTs were 1.2 and 1.8 higher than those observed in the qHPV group (both P < 0.01). In bHPV group a 1.4–1.6-fold increase of antibody GMTs to HPV6 and HPV11was also observed (P < 0.001). The safety profile was acceptable for both vaccines. Both qHPV and bHPV increase antibody titers when given as a booster to girls previously vaccinated with 2 doses of qHPV. The magnitude of the immune response after booster is vaccine-dependent and has the same pattern as that reported after primary vaccination with qHPV or bHPV. When given as a booster, both vaccines have an acceptable safety profile. Longer follow-up studies are warranted to assess the need of booster doses. PMID:25714044

  9. Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose schedule compared with the licensed 3-dose schedule

    PubMed Central

    Schwarz, Tino F; Ferguson, Linda M; Peters, Klaus; Dionne, Marc; Schulze, Karin; Ramjattan, Brian; Hillemanns, Peter; Catteau, Grégory; Dobbelaere, Kurt; Schuind, Anne; Descamps, Dominique

    2011-01-01

    The immunogenicity of the human papillomavirus (HPV)-16/18 AS 04-adjuvanted vaccine (Cervarix®, GlaxoSmithKline Biologicals) administered according to its licensed vaccination schedule (3-dose, 3D) and formulation (20 µg of each HPV antigen; 20/20F) has previously been demonstrated. This partially-blind, controlled, randomized trial (NCT00541970) evaluated 2-dose (2D) schedules using the licensed 20/20F or an alternative formulation containing 40 µg of each antigen (40/40F), compared with the licensed 3D schedule. Healthy females stratified by age (9–14, 15–19, 20–25 y) were randomized to receive 2 doses of 20/20F at Months (M) 0,6 (n = 240), 40/40F at M0,6 (n = 241) or 40/40F at M0,2 (n = 240), or 3 doses of 20/20F at M0,1,6 (licensed schedule/formulation, n = 239). One month after the last dose, the 3D schedule was not immunologically superior to 2D schedules except in the 40/40F M0,2 group for HPV-16 (lower limit of 95% CI geometric mean antibody titer (GMT) ratio [2D/3D] <0.5). For both HPV-16 and HPV-18, the 2D schedules in girls 9–14 y were immunologically non-inferior to the 3D schedule in women 15–25 y (the age group in which efficacy has been demonstrated) (upper limit of 95% CI for GMT ratio [3D/2D] <2) one month after the last dose. At Month 24, non-inferiority was maintained for the 2D M0,6 schedules in girls 9–14 y vs. the 3D schedule in women 15–25 y. All formulations had acceptable reactogenicity and safety profiles. These results indicate that the HPV-16/18 vaccine on a 2D M0,6 schedule is immunogenic and generally well tolerated in girls 9–14 y and that the 2D schedule is likely adequate for younger females. PMID:22048171

  10. Efficacy of ketoprofen administered in drinking water at a low dose for the treatment of porcine respiratory disease complex.

    PubMed

    Salichs, M; Sabaté, D; Homedes, J

    2013-09-01

    The purpose of this study was to evaluate the efficacy of an oral solution of ketoprofen administered in drinking water at a lower dose as a complement to antimicrobial therapy in a mild outbreak of porcine respiratory disease complex. The study was performed with 120 pigs with rectal temperature between 39.9 and 41°C and at least 1 sign indicating porcine respiratory disease complex (dyspnea, cough, nasal discharge, or depression). Animals were randomly allocated in 2 groups (treated and control group). Animals in both groups received etiological therapy with doxycycline at 10 mg · kg(-1) in drinking water for 5 d. The animals in the treated group also received 1.5 mg · kg(-1) of ketoprofen during the first 3 d. The reduction in rectal temperature in the treated group was significantly greater during the days of ketoprofen administration and up to 1 d after the end of treatment (P < 0.05). The percentage of dyspneic animals was significantly less (P < 0.05) in the treated group from d 2 to 5 of the study. Also, a significant improvement regarding depression and cough was seen in the animals of the treated group. No statistically significant (P > 0.05) differences were evidenced in productive variables. In conclusion, oral treatment with ketoprofen at 1.5 mg · kg(-1) in combination with antimicrobial therapy was found to be a clinically effective approach in outbreaks of mild porcine respiratory disease complex. PMID:23825328

  11. Ingestion and excretion of arsenic compounds present in edible brown algae, Hijikia fusiforme, by mice.

    PubMed

    Ichikawa, Satoshi; Nozawa, Shihoko; Hanaoka, Ken'ichi; Kaise, Toshikazu

    2010-02-01

    The element arsenic is a carcinogen and toxic for humans and other living organisms. Some seaweeds contain high amounts of inorganic arsenic (iAs). In particular, Hijikia fusiforme has a high iAs content of approximately 50%. In this study, we examined the absorption, metabolism, excretion, and accumulation of arsenic compounds in mice after the administration of Hijiki. The single-dose experiment, wherein a single dose of cooked Hijiki was administered to the mice, revealed that the urinary and fecal excretion of arsenic compounds was the highest on the first day of dosing, and it became clear that 66-92% of arsenic was excreted within 3 days after administration of the first dose. The repeated-dose experiment, wherein repeated doses of cooked or dried Hijiki were administered to the mice, arsenic was detected in all the tissues, but only approximately 5% of the administered dose of arsenic was detected as residual arsenic. These results suggest that the arsenic present in cooked Hijiki is accumulated in very small amounts in mice. PMID:19808076

  12. Immune response to the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose or 3-dose schedule up to 4 years after vaccination

    PubMed Central

    Romanowski, Barbara; Schwarz, Tino F; Ferguson, Linda M; Ferguson, Murdo; Peters, Klaus; Dionne, Marc; Schulze, Karin; Ramjattan, Brian; Hillemanns, Peter; Behre, Ulrich; Suryakiran, Pemmaraju; Thomas, Florence; Struyf, Frank

    2014-01-01

    This randomized, partially-blind study (ClinicalTrials.gov registration number NCT00541970) evaluated the immunogenicity and safety of 2-dose (2D) schedules of the HPV-16/18 AS04-adjuvanted vaccine. Results to month (M) 24 have been reported previously and we now report data to M48 focusing on the licensed vaccine formulation (20 μg each of HPV-16 and -18 antigens) administered at M0,6 compared with the standard 3-dose (3D) schedule (M0,1,6). Healthy females (age stratified: 9–14, 15–19, 20–25 years) were randomized to receive 2D at M0,6 (n = 240) or 3D at M0,1,6 (n = 239). In the according-to-protocol immunogenicity cohort, all initially seronegative subjects seroconverted for HPV-16 and -18 antibodies and remained seropositive up to M48. For both HPV-16 and -18, geometric mean antibody titer (GMT) ratios (3D schedule in women aged 15–25 years divided by 2D schedule in girls aged 9–14 years) at M36 and M48 were close to 1, as they were at M7 when non-inferiority was demonstrated. The kinetics of HPV-16, -18, -31, and -45 antibody responses were similar for both groups and HPV-16 and -18 GMTs were substantially higher than natural infection titers. The vaccine had a clinically acceptable safety profile in both groups. In summary, antibody responses to a 2D M0,6 schedule of the licensed vaccine formulation in girls aged 9–14 years appeared comparable to the standard 3D schedule in women aged 15–25 years up to 4 years after first vaccination. A 2D schedule could facilitate implementation of HPV vaccination programs and improve vaccine coverage and series completion rates. PMID:24576907

  13. Absorption, distribution and excretion of the colour fraction of Caramel Colour IV in the rat.

    PubMed

    Selim, S; Chappel, C I; Schoenig, G P

    1992-05-01

    Caramel Colour IV prepared from [U-14C]glucose was ultrafiltered in order to isolate the high molecular weight colour fraction (HMCF). The colour fraction that was non-permeable to a 10,000-Da porosity membrane, contained 84% of the colour, 22% of the solids and 24% of the radioactivity of the [14C]Caramel Colour IV. The absorption, distribution and excretion of [14C]HMCF were evaluated in male rats after administration of single or multiple oral doses of the material at a dosage level of 2.5 g/kg body weight. Rats on the multiple oral dosage regimen were given unlabelled HMCF in their drinking water for 13 days before the administration of a bolus dose of [14C]HMCF on day 14. On both dosage regimens, the predominant route of excretion was by way of the faeces. Less than 3% of the administered radioactivity was excreted in the urine and only a negligible amount was found in the expired air. More than 99% of the administered radioactivity was excreted within 96 hr. The principal tissues in which radioactivity was found were the mesenteric lymph nodes, liver, kidney and tissues of the gastro-intestinal tract. No major differences were observed in the absorption, distribution or excretion patterns between the single and multiple oral dose regimens. PMID:1644386

  14. Potassium bicarbonate supplementation lowers bone turnover and calcium excretion in older men and women a randomized dose-finding trial

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The acid load accompanying modern diets may have adverse effects on bone and muscle metabolism. Treatment with alkaline salts of potassium can neutralize the acid load, but the optimal amount of alkali is not established. Our objective was to determine the effectiveness of two doses of potassium bic...

  15. Faecal excretion dynamic during subacute oral exposure to different Pb species in Rattus norvegicus.

    PubMed

    Cadková, Zuzana; Száková, Jiřina; Miholová, Daniela; Válek, Petr; Pacáková, Zuzana; Vadlejch, Jaroslav; Langrová, Iva; Jankovská, Ivana

    2013-05-01

    Faecal excretion is a basic means of detoxification upon ingestion of Pb-contaminated feed. In order to determine a time course of Pb elimination after oral exposure to two different forms of this heavy metal (lead acetate vs. phyto-bound Pb), a feeding study was carried out in experimental rats using the Pb phyto-hyperaccumulator Pistia stratiotes as a model diet. The effect of starvation on Pb excretion was further studied in rats that were fed plant material. Twelve Pb doses (7 μg Pb/1 g BW) were administered orally over a 5-week period. Faeces samples were collected 24 and 72 h post-exposure. Inductively coupled plasma optical emission spectrometry and electrothermal absorption spectrometry methods were used for determination of heavy metal concentrations. Up to 53 % of ingested Pb was rapidly eliminated from the exposed rats via faeces within 24 h after exposure. Faecal excretion in exposed rats differed significantly when compared to that of the control group. Fasting before exposure reduced Pb excretion by up to 50 %. Faecal excretions of both examined Pb forms exhibited almost identical patterns. Considerable differences were revealed concerning total excretion levels; lead acetate was excreted in amount greater extent than those of phytobound Pb. Results of our study suggest that Pb forms occurring in the P. stratiotes tissues are absorbed through the gastrointestinal tract to a greater extent than Pb from lead acetate. Therefore, higher portions of ingested Pb can be available for potential accumulation in tissues of exposed subjects. PMID:23408261

  16. Atypical excretion profile and GC/C/IRMS findings may last for nine months after a single dose of nandrolone decanoate.

    PubMed

    Palonek, Elzbieta; Ericsson, Magnus; Gårevik, Nina; Rane, Anders; Lehtihet, Mikael; Ekström, Lena

    2016-04-01

    The use of the anabolic androgenic steroid nandrolone and its prohormones is prohibited in sport. A common route of nandrolone administration is intramuscular injections of a nandrolone ester. Here we have investigated the detection time of nandrolone and 19-norandrosterone and 19-noretiocholanolone metabolites in eleven healthy men after the administration of a 150 mg dose of nandrolone decanoate. The urinary concentrations of nandrolone and the metabolites were monitored by GC-MS/MS for nine months and in some samples the presence of 19-norandrosterone was confirmed by GC/C/IRMS analysis. The participants were genotyped for polymorphisms in PDE7B1 and UGT2B15 genes previously shown to influence the activation and inactivation of nandrolone decanoate. There were large inter-individual variations in the excretion rate of nandrolone and the metabolites, although not related to genetic variations in the UGT2B15 (rs1902023) and PDE7B1 (rs7774640) genes. After the administration, 19-norandrosterone was found at 2-8-fold higher concentrations than 19-noretiocholanolone. We showed that nandrolone doping can be identified 4 and 9 months after the injection of only one single dose in six and three individuals, respectively. We also noted that GC/C/IRMS confirms the presence of exogenous 19-norandrosterone in the urine samples, showing δ13 values around -32 ‰. This was true even in a sample that was not identified as an atypical finding after the GC-MS/MS analysis further showing the power of using GC/C/IRMS in routine anti-doping settings. PMID:26853157

  17. XG-102 administered to healthy male volunteers as a single intravenous infusion: a randomized, double-blind, placebo-controlled, dose-escalating study

    PubMed Central

    Deloche, Catherine; Lopez-Lazaro, Luis; Mouz, Sébastien; Perino, Julien; Abadie, Claire; Combette, Jean-Marc

    2014-01-01

    The aim of the study is to evaluate the safety, tolerability and pharmacokinetics (PK) of the JNK inhibitor XG-102 in a randomized, double blind, placebo controlled, sequential ascending dose parallel group Phase 1 Study. Three groups of male subjects received as randomly assigned ascending single XG-102 doses (10, 40, and 80 μg/kg; 6 subjects per dose) or placebo (2 subjects per dose) as an intravenous (IV) infusion over 60 min. Safety and tolerability were assessed by physical examination, vital signs, electrocardiography, eye examination, clinical laboratory tests and adverse events (AEs). PK was analyzed using noncompartmental methods. All reported AEs were mild to moderate and neither their number nor their distribution by System Organ Class suggest a dose relationship. Only headache and fatigue were considered probably or possibly study drug related. Headache frequency was similar for active and placebo, consequently this was not considered to be drug related but probably to study conditions. The other examinations did not show clinically relevant deviations or trends suggesting a XG-102 relationship. Geometric mean half-life was similar among doses, ranging from 0.36 to 0.65 h. Geometric mean XG-102 AUC0–last increased more than linearly with dose, 90% confidence intervals (CIs) did not overlap for the two highest doses. Geometric mean dose normalized Cmax values suggest a more than linear increase with dose but 90% CIs overlap. It may be concluded that XG-102 single IV doses of 10–80 μg/kg administered over 1 h to healthy male subjects were safe and well tolerated. PMID:25505576

  18. Purine and pyrimidine excretion in psoriasis

    PubMed Central

    Simmonds, H. A.; Bowyer, A.

    1974-01-01

    1 Urinary purine excretion has been investigated in two healthy controls and two patients with psoriasis, one a hyperuricaemic, one a normouricaemic. No difference was detected between the patients and controls. Therapy with allopurinol effectively lowered blood and urinary uric acid levels and produced a deficit in total urinary oxypurine excretion in both controls and patients with psoriasis. The concomitant increase in xanthine excretion was greater than the increase in hypoxanthine excretion and xanthine/hypoxanthine ratios (average 0.70 and 1.0 prior to therapy) were increased by allopurinol to an average of 3.0 and 3.8 respectively in the two groups. Allopurinol also reduced the excretion of 8-hydroxy-7-methyl guanine but no effect on the excretion levels of other minor purine bases was noted. 2 Allopurinol was metabolized similarly by both patients and controls, 84% of the administered allopurinol being accounted for as urinary metabolites. 74% of the drug in the urine was excreted as oxipurinol, 26% as unchanged allopurinol plus allopurinol riboside, the remainder being oxipurinol riboside. 3 Pseudouridine excretion in 25 healthy controls was 86.5 ± 17.8 mg/24 hours. Pseudouridine excretion was not excessive in the patients with psoriasis and was not altered by allopurinol therapy. 4 No abnormality or difference in purine or pyrimidine excretion in either patient was detected prior to or during therapy which could be related to the epidermal lesion. PMID:22454896

  19. Dosing and Safety Implications for Oncologists When Administering Everolimus to Patients With Hormone Receptor-Positive Breast Cancer.

    PubMed

    Rugo, Hope S

    2016-02-01

    Aberrations in the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway are common abnormalities in breast cancer and are associated with the development of resistance to endocrine- and human epidermal growth factor receptor (HER)2-targeted therapies. Because of the significant improvement in progression-free survival for everolimus plus exemestane compared with exemestane plus placebo, everolimus, an mTOR inhibitor, was approved in the United States for the treatment of patients with hormone receptor-positive (HR+), HER-negative, advanced breast cancer whose disease had progressed while receiving letrozole or anastrozole. To provide optimal prevention and management strategies, it is crucial that clinicians are aware of the adverse events (AEs) associated with mTOR inhibition. Understanding the appropriate dose modifications will help reduce toxicity and improve drug tolerance, thus achieving the optimal benefit from everolimus. Analyses of data from the Breast Cancer Trials of Oral Everolimus 2 trial have shown that, despite a greater frequency of AEs in the everolimus plus exemestane treatment arm, the AEs were effectively managed with temporary dose reductions or interruptions. In some cases, the full dose of everolimus could be resumed. Despite a lower mean dose and duration of exposure in patients aged ≥ 70 versus < 70 years, everolimus plus exemestane was similarly efficacious, suggesting that appropriate dose reductions for toxicity will not adversely impact efficacy. Appropriate modification of the everolimus dose and dose delay according to the severity of AEs, with resumption of the optimal dose of everolimus when toxicity has improved, will positively affect patient outcomes in HR+ advanced breast cancer. PMID:26507507

  20. Estimating the intake of abused methamphetamines using experimenter-administered deuterium labeled R-methamphetamine: selection of the R-methamphetamine dose.

    PubMed

    Li, Linghui; Lopez, Juan Carlos; Galloway, Gantt P; Baggott, Matthew J; Everhart, Tom; Mendelson, John

    2010-08-01

    All addictive drugs produce tolerance and addicts compensate by increasing drug exposure. Thus, the quantity of illicit drug ingested is related to the severity of addiction. Unfortunately, there are no objective methods to estimate intake for most addictive drugs. Using experimenter-administered doses of deuterium-labeled R-methamphetamine (R-[-]-MA-d3), we have developed a method to estimate the amount of abused methamphetamine intake in addicts enrolled in clinical trials. This study assessed the pharmacokinetics, pharmacodynamics, and tolerability of single oral doses of R-MA in healthy adults to select a dose of R-MA-d3 to be used as a biomarker for estimation the amount of methamphetamine abuse. This was a five-session randomized, double-blind, placebo-controlled, balanced crossover study in eight subjects. Oral R-(-)-MA was dosed at 0 mg, 1 mg, 2.5 mg, 5 mg, or 10 mg; bioavailability was estimated by slow intravenous dosing (30 minutes) of 2.5 mg R-(-)-MA-d3 given with the 2.5 mg R-(-)-MA oral dose condition. Pharmacokinetic and pharmacodynamic measures were obtained. No serious adverse events occurred during the study and all doses of R-MA were well tolerated. Linear pharmacokinetics was observed within our oral dose range of 1 to 10 mg. Complete bioavailability and pharmacologic inactivity were found for all oral doses. These characteristics indicate the advantage of using a small oral R-(-)-MA-d3 dose as a biomarker to estimate exposure to abused methamphetamine. Based on these results, 5 mg R-(-)-MA-d3 has been selected as the biomarker dose in future studies. Preliminary findings from our study indicate that experimenter-administered oral R-(-)-MA-d3 may allow estimation of abused methamphetamine intake and exposure. Knowledge of the quantity of methamphetamine intake may allow better estimation of disease severity and treatment efficacy. Experience gained from this study also can be applied to the management of other drug dependence problems such as

  1. American Society for Pain Management Nursing Position Statement: Prescribing and Administering Opioid Doses Based Solely on Pain Intensity.

    PubMed

    Pasero, Chris; Quinlan-Colwell, Ann; Rae, Diana; Broglio, Kathleen; Drew, Debra

    2016-06-01

    The foundation of safe and effective pain management is an individualized, comprehensive pain assessment, which includes, but is not limited to, determining the intensity of pain if the patient is able to report it. An unforeseen consequence of the widespread use of pain intensity rating scales is the practice of prescribing specific doses of opioid analgesics based solely on specific pain intensity. Many factors in addition to pain intensity influence opioid requirements, and there is no research showing that a specific opioid dose will relieve pain of a specific intensity in all patients. The American Society for Pain Management Nursing (ASPMN) holds the position that the practice of prescribing doses of opioid analgesics based solely on a patient's pain intensity should be prohibited because it disregards the relevance of other essential elements of assessment and may contribute to untoward patient outcomes. PMID:27108082

  2. Dose- (and time-) dependent blockade of pregnancy in Sprague-Dawley rats administered ammonium dinitramide in drinking water.

    PubMed

    Kinkead, E R; Wolfe, R E; Feldmann, M L

    1996-01-01

    Ammonium dinitramide (ADN) is a class 1.1 explosive oxidizer that can be used in solid rocket propellant mixtures and explosives. A 90-day general toxicity/ reproductive screen performed on this compound at doses of 162, 103, 29, and 0.0 mg ADN/kg/day resulted in a treatment-related adverse effect on litter production. Incidences of animals producing litters (1/11, 3/12, 12/12, and 11/12, respectively) and mean numbers of pups per litter (7, 7, 16, and 15, respectively) both were statistically significantly less than controls. In a follow-up study, mated dams treated with ADN at the same doses and examined at gestation days (GDs) 10 and 20 showed an effect in fetus loss similar to that seen in the reproductive screen. A pre- versus postimplantation dosing regimen indicated that implantation is vulnerable to ADN effects during the preimplantation period (GDs 1-3). No implantation sites were found in the rats treated with 2000 mg ADN/L drinking water (target dose of 160 mg ADN/kg/day) during GDs 1-3. Numbers of implantation sites found in the rats treated during GDs 4-8 were similar to those found in the control group. The pituitary was not identified specifically in this study as the site of primary action, but serum progesterone was reduced by 27%, which may have resulted in reduced fertility. PMID:8713714

  3. Systemic Absorption of Rifamycin SV MMX Administered as Modified-Release Tablets in Healthy Volunteers▿

    PubMed Central

    Di Stefano, A. F. D.; Rusca, A.; Loprete, L.; Dröge, M. J.; Moro, L.; Assandri, A.

    2011-01-01

    The new oral 200-mg rifamycin SV MMX modified-release tablets, designed to deliver rifamycin SV directly into the colonic lumen, offer considerable advantages over the existing immediate-release antidiarrheic formulations. In two pharmacokinetics studies of healthy volunteers, the absorption, urinary excretion, and fecal elimination of rifamycin SV after single- and multiple-dose regimens of the new formulation were investigated. Concentrations in plasma of >2 ng/ml were infrequently and randomly quantifiable after single and multiple oral doses. The systemic exposure to rifamycin SV after single and multiple oral doses of MMX tablets under fasting and fed conditions or following a four-times-a-day (q.i.d.) or a twice-a-day (b.i.d.) regimen could be considered negligible. With both oral regimens, the drug was confirmed to be very poorly absorbable systemically. The amount of systemically absorbed antibiotic excreted by the renal route is far lower than 0.01% of the administered dose after both the single- and multiple-dose regimens. The absolute bioavailability, calculated as the mean percent ratio between total urinary excretion amounts (ΣXu) after a single intravenous injection and after a single oral dose under fasting conditions, was 0.0410 ± 0.0617. The total elimination of the unchanged rifamycin SV with feces was 87% of the administered oral dose. No significant effect of rifamycin SV on vital signs, electrocardiograms, or laboratory parameters was observed. PMID:21402860

  4. PHARMACOKINETICS OF TRAMADOL HYDROCHLORIDE AND ITS METABOLITE O-DESMETHYLTRAMADOL FOLLOWING A SINGLE, ORALLY ADMINISTERED DOSE IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS).

    PubMed

    Boonstra, Jennifer L; Barbosa, Lorraine; Van Bonn, William G; Johnson, Shawn P; Gulland, Frances M D; Cox, Sherry K; Martin-Jimenez, Tomas

    2015-09-01

    Tramadol is a synthetic, centrally acting, opiate-like analgesic that is structurally related to codeine and morphine. The objective of this study was to determine the pharmacokinetics of tramadol hydrochloride and its major active metabolite O-desmethyltramadol (M1) in the California sea lion (Zalophus californianus). A single dose of tramadol was administered orally in fish at 2 mg/kg to a total of 15 wild California sea lions admitted for rehabilitation. Twenty-four total blood samples were collected post drug administration at 10, 20, 30, and 45 min and at 1, 3, 5, 6, 8, 12, and 24 hr. Blood plasma was separated and stored at -80°C until analysis with high-performance liquid chromatography was performed to determine levels of tramadol and M1, the major active metabolite. The results indicate that the plasma levels of parent tramadol are low or negligible during the first 30-45 min and then reach the predicted mean maximum plasma concentration of 358 ng/ml at 1.52 hr. The M1 metabolite was not detectable in 21 of 24 plasma samples, below the level of quantification of 5 ng/ml in one sample, and detectable at 11 and 17 ng/ml in two of the samples. This study suggests that a 2 mg/kg dose would need to be administered every 6-8 hr to maintain concentrations of tramadol above the minimum human analgesic level for mild to moderate pain. Based on dosing simulations, a dose of 4 mg/kg q8 hr or q12 hr, on average, may represent an adequate compromise, but further studies are needed using a larger sample size. Pharmacodynamic studies are warranted to determine if tramadol provides analgesic effects in this species. The potential for tramadol toxicosis at any dose also has not been determined in this species. PMID:26352950

  5. Ferrioxamine excretion in iron-loaded man

    SciTech Connect

    Pippard, M.J.; Callender, S.T.; Finch, C.A.

    1982-08-01

    Factors affecting iron excretion after subcutaneous desferrioxamine infusion were evaluated in individuals with iron overload. Urinary iron varied directly, whereas stool iron varied inversely with the level of erythropoiesis. Ascorbic acid greatly enhanced urinary iron excretion but had a less constant effect on stool iron. Stool iron losses contributed a greater proportion of total iron excretion at higher chelator dosage. These studies indicate the importance of biliary iron excretion in monitoring the effectiveness of desferrioxamine. They also suggest that large chelator doses may remove established iron overload much more rapidly than has previously been realized.

  6. [Antiradiation and toxic effect of ATP, AET and serotonin administered in combination to mice. Optimal relations between component doses].

    PubMed

    Benova, D K

    1983-01-01

    It was established that the optimal dose ratio (high effectiveness and minimum toxicity) between the components in the combination: serotonin/AET/ATP was 1/3/45. It was shown that the radioprotective effect was conditioned by AET and serotonin the latter being more significant. ATP played a minor role in the total protective effect decreasing however, the toxicity of the combination. PMID:6611880

  7. Quantitative Evaluation of Compliance with Recommendation for Sulfonylurea Dose Co-Administered with DPP-4 Inhibitors in Japan.

    PubMed

    Kimura, Tomomi; Shiosakai, Kazuhito; Takeda, Yasuaki; Takahashi, Shinji; Kobayashi, Masahiko; Sakaguchi, Motonobu

    2012-01-01

    After the launch of dipeptidyl peptidase-4 (DPP-4), a new oral hypoglycemic drug (OHD), in December 2009, severe hypoglycemia cases were reported in Japan. Although the definite cause was unknown, co-administration with sulfonylureas (SU) was suspected as one of the potential risk factors. The Japan Association for Diabetes Education and Care (JADEC) released a recommendation in April 2010 to lower the dose of three major SUs (glimepiride, glibenclamide, and gliclazide) when adding a DPP-4 inhibitor. To evaluate the effectiveness of this risk minimization action along with labeling changes, dispensing records for 114,263 patients prescribed OHDs between December 2008 and December 2010 were identified in the Nihon-Chouzai pharmacy claims database. The adherence to the recommended dosing of SU co-prescribed with DPP-4 inhibitors increased from 46.3% before to 63.8% after the JADEC recommendation (p < 0.01 by time-series analysis), while no change was found in those for SU monotherapy and SU with other OHD co-prescriptions. The adherence was significantly worse for those receiving a glibenclamide prescription. The JADEC recommendation, along with labeling changes, appeared to have a favorable effect on the risk minimization action in Japan. In these instances, a pharmacy claims database can be a useful tool to evaluate risk minimization actions. PMID:24300302

  8. The effects of midazolam and butorphanol, administered alone or combined, on the dose and quality of anaesthetic induction with alfaxalone in goats.

    PubMed

    Dzikiti, T Brighton; Zeiler, Gareth E; Dzikiti, Loveness N; Garcia, Eva R

    2014-01-01

    Goats are rarely anaesthetised; consequently, scant information is available on the efficacy of anaesthetic drugs in this species. Alfaxalone is a relatively new anaesthetic agent, of which the efficacy in goats has not yet been studied. In this study, the sedative and alfaxalone sparing effects of midazolam and butorphanol, administered alone or concomitantly, in goats were assessed. Eight clinically healthy goats, four does and four wethers, were enlisted in a randomised crossover manner to receive intramuscular sedative treatments consisting of saline 0.05 mL/kg, or midazolam 0.30 mg/kg, or butorphanol 0.10 mg/kg, or a combination of midazolam 0.30 mg/kg with butorphanol 0.10 mg/kg before intravenous induction of general anaesthesia with alfaxalone. Following induction, the goats were immediately intubated and the quality of anaesthesia and basic physiological cardiorespiratory and blood-gas parameters were assessed until the goats had recovered from anaesthesia. The degree of sedation, quality of induction and recovery were scored. When compared with saline (3.00 mg/kg), midazolam,administered alone or with butorphanol, caused a statistically significant increased level of sedation and a reduction in the amount of alfaxalone required for induction (2.00 mg/kg and 1.70 mg/kg, respectively). Butorphanol alone (2.30 mg/kg) did not cause significant changes in level of sedation or alfaxalone-induction dose. During induction and recovery, the goats were calm following all treatments, including the control group. Cardiorespiratory and blood-gas parameters were maintained within clinically acceptable limits. The present study showed that midazolam, administered alone or combined with butorphanol, produces a degree of sedation that significantly reduces the dose of alfaxalone required for induction of general anaesthesia in goats, without causing any major adverse cardiorespiratory effects. PMID:25686277

  9. Multiple-dose pharmacokinetics of intravenously administered cefoperazone and sulbactam when given in combination to infected, seriously ill, elderly patients.

    PubMed Central

    Schwartz, J I; Jauregui, L E; Bachmann, K A; Martin, M E; Reitberg, D P

    1988-01-01

    The pharmacokinetics of cefoperazone and sulbactam in combination were evaluated in six, elderly, seriously ill patients treated with the drug combination for intra-abdominal infections. After giving informed consent, three males and three females aged 63.5 to 77.5 (mean 67.9) years and weighing 54.5 to 86.8 (mean, 67.6) kg were treated with cefoperazone (2.0 g) and sulbactam (1.0 g) infused intravenously every 12 h for at least 5 days. Cefoperazone and sulbactam pharmacokinetics were characterized on both days 1 and 5 of treatment. Eleven serial blood samples were obtained just prior to and following dose 1 on days 1 and 5 of treatment. Mean estimates of cefoperazone maximal concentration in plasma (Cmax), area under the curve of drug concentration in plasma versus time (AUC), half-life (t 1/2), apparent volume of distribution by the area method (Varea), apparent volume of distribution at steady state (Vss), and total body clearance (CL) for day 1 (day 5) were 297.5 237.5) micrograms/ml, 1,247 (1,063) micrograms.h/ml, 7.0 (4.9) h, 16.1 (13.4) liter, 13.1 (14.4) liter, and 28.9 (34.2) ml/min, respectively. Day 1 (day 5) mean values for sulbactam Cmax, AUC, t 1/2, Varea, Vss, and CL were 110.3 (78.0) micrograms/ml, 228 (217) micrograms.h/ml, 3.4 (2.5) h, 26.1 (18.5) liter, 18.9 (15.4) liter, and 97 (94) ml/min, respectively. Both drugs evidenced slower elimination and greater pharmacokinetic variability in these patients compared with values previously reported for normal volunteers. As patients improved during the course of therapy, the only pharmacokinetic parameter significantly changed between days 1 and 5 was a shortened sulbactam t 1/2. Our inability to find substantial evidence of pharmacokinetic normalization may have been related to sample size and study duration. Both drugs were present in potentially therapeutic concentrations for the entire 12-h dosing interval, but without undue accumulation from days 1 to 5. PMID:3395103

  10. Tissue dosimetry, metabolism and excretion of pentavalent and trivalent dimethylated arsenic in mice after oral administration

    SciTech Connect

    Hughes, Michael F. Devesa, Vicenta; Adair, Blakely M.; Conklin, Sean D.; Creed, John T.; Styblo, Miroslav; Kenyon, Elaina M.; Thomas, David J.

    2008-02-15

    Dimethylarsinic acid (DMA(V)) is a rat bladder carcinogen and the major urinary metabolite of administered inorganic arsenic in most mammals. This study examined the disposition of pentavalent and trivalent dimethylated arsenic in mice after acute oral administration. Adult female mice were administered [{sup 14}C]-DMA(V) (0.6 or 60 mg As/kg) and sacrificed serially over 24 h. Tissues and excreta were collected for analysis of radioactivity. Other mice were administered unlabeled DMA(V) (0.6 or 60 mg As/kg) or dimethylarsinous acid (DMA(III)) (0.6 mg As/kg) and sacrificed at 2 or 24 h. Tissues (2 h) and urine (24 h) were collected and analyzed for arsenicals. Absorption, distribution and excretion of [{sup 14}C]-DMA(V) were rapid, as radioactivity was detected in tissues and urine at 0.25 h. For low dose DMA(V) mice, there was a greater fractional absorption of DMA(V) and significantly greater tissue concentrations of radioactivity at several time points. Radioactivity distributed greatest to the liver (1-2% of dose) and declined to less than 0.05% in all tissues examined at 24 h. Urinary excretion of radioactivity was significantly greater in the 0.6 mg As/kg DMA(V) group. Conversely, fecal excretion of radioactivity was significantly greater in the high dose group. Urinary metabolites of DMA(V) included DMA(III), trimethylarsine oxide (TMAO), dimethylthioarsinic acid and trimethylarsine sulfide. Urinary metabolites of DMA(III) included TMAO, dimethylthioarsinic acid and trimethylarsine sulfide. DMA(V) was also excreted by DMA(III)-treated mice, showing its sensitivity to oxidation. TMAO was detected in tissues of the high dose DMA(V) group. The low acute toxicity of DMA(V) in the mouse appears to be due in part to its minimal retention and rapid elimination.

  11. Clinical study of urinary excretion of Ga-67

    SciTech Connect

    Nakano, S.; Hasegawa, Y.; Ibuka, K.; Hashizume, T.; Noguchi, A.; Kojima, J.; Sasakuma, F.; Ishigami, S. )

    1990-04-01

    Ga-67 urinary excretion was examined in 59 patients. The 72-hour urinary excretion rate ranged from 4.3 to 67.8% of the injected dose. Within the first 24 hours, 60.9% of the 72-hour urinary excretion was excreted. There was no significant difference in the Ga-67 urinary excretion rate between males and females, nor between the Ga-67 positive and negative cases. A significant negative correlation was found between the 72-hour Ga-67 urinary excretion rate and the unsaturated iron binding capacity. Notably, four patients with hyperferremia, which was considered secondary to leukemia and/or chemotherapy or liver cirrhosis, excreted more than 46.8% of Ga-67 within 72 hours. A significant negative correlation was also found between the 72-hour Ga-67 urinary excretion rate and age. Urinary excretion of Ga-67 may be related to the glomerular filtration rate, which decreases with age.

  12. Disposition of disodium cromoglycate administered in three particle sizes.

    PubMed Central

    Curry, S H; Taylor, A J; Evans, S; Godfrey, S; Zeidifard, E

    1975-01-01

    1 Disodium cromoglycate (DSCG) was administered in three particle sizes to five human subjects. 2 Urinary excretion of DSCG, as a proportion of the dose, was highest following small particles; the lower values recorded following intermediate-sized and large particles were similar. 3 DSCG deposited in the mouth was highest following large particles; the lower values recorded following intermediate-sized and small particles were similar. 4 The data were examined in relation to the recent observation that the protective effect of small particles of DSCG is dramatically superior to that of large particles. PMID:825134

  13. Neoadjuvant Sequential Docetaxel Followed by High-Dose Epirubicin in Combination With Cyclophosphamide Administered Concurrently With Trastuzumab. The DECT Trial.

    PubMed

    Pizzuti, Laura; Barba, Maddalena; Giannarelli, Diana; Sergi, Domenico; Botti, Claudio; Marchetti, Paolo; Anzà, Michele; Maugeri-Saccà, Marcello; Natoli, Clara; Di Filippo, Simona; Catenaro, Teresa; Tomao, Federica; Amodio, Antonella; Carpano, Silvia; Perracchio, Letizia; Mottolese, Marcella; Di Lauro, Luigi; Sanguineti, Giuseppe; Di Benedetto, Anna; Giordano, Antonio; Vici, Patrizia

    2016-11-01

    To report the results of the DECT trial, a phase II study of locally advanced or operable HER2-positive breast cancer (BC) treated with taxanes and concurrent anthracyclines and trastuzumab. Eligible patients (stage IIA-IIIB HER2-positive BC, 18-75 years, normal organ functions, ECOG ≤1, and left ventricular ejection fraction (LVEF) ≥55%) received four cycles of neoadjuvant docetaxel, 100 mg/m(2) intravenously, plus trastuzumab 6 mg/kg (loading dose 8 mg/kg) every 3 weeks, followed by four 3-weekly cycles of epirubicin 120 mg/m(2) and cyclophosphamide, 600 mg/m(2) , plus trastuzumab. Primary objective was pathologic complete response (pCR) rate, defined as ypT0/is ypN0 at definitive surgery. We enrolled 45 consecutive patients. All but six patients (13.3%) completed chemotherapy and all underwent surgery. pCR was observed in 28 patients (62.2%) overall and in 6 (66.7%) from the inflammatory subgroup. The classification and regression tree analysis showed a 100% pCR rate in patients with BMI ≥25 and with hormone negative disease. The median follow up was 46 months (8-78). Four-year recurrence-free survival was 74.7% (95%CI, 58.2-91.2). Seven patients (15.6%) recurred and one died. Treatment was well tolerated, with limiting toxicity being neutropenia. No clinical cardiotoxicity was observed. Six patients (13.4%) showed a transient LVEF decrease (<10%). In one patient we observed a ≥10% asymptomatic LVEF decrease persisting after surgery. Notwithstanding their limited applicability due to the current guidelines, our findings support the efficacy of the regimen of interest in the neoadjuvant setting along with a fairly acceptable toxicity profile, including cardiotoxicity. Results on BMI may invite further assessment in future studies. J. Cell. Physiol. 231: 2541-2547, 2016. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc. PMID:27187274

  14. Multicenter Study of Decitabine Administered Daily for 5 Days Every 4 Weeks to Adults With Myelodysplastic Syndromes: The Alternative Dosing for Outpatient Treatment (ADOPT) Trial

    PubMed Central

    Steensma, David P.; Baer, Maria R.; Slack, James L.; Buckstein, Rena; Godley, Lucy A.; Garcia-Manero, Guillermo; Albitar, Maher; Larsen, Julie S.; Arora, Sujata; Cullen, Michael T.; Kantarjian, Hagop

    2009-01-01

    Purpose Decitabine, a DNA-targeted hypomethylating agent, is approved by the United States Food and Drug Administration for treatment of patients with myelodysplastic syndromes (MDS) on a schedule of 15 mg/m2 administered via intravenous (IV) infusion every 8 hours for 3 days. This study assessed the efficacy and safety of an alternative dosing regimen administered on an outpatient basis in academic and community-based practices. Patients and Methods Patients were treated with decitabine 20 mg/m2 by IV infusion daily for 5 consecutive days every 4 weeks. Eligible patients were ≥ 18 years of age and had MDS (de novo or secondary) of any French-American-British (FAB) subtype and an International Prognostic Scoring System (IPSS) score ≥ 0.5. The primary end point was the overall response rate (ORR) by International Working Group (IWG 2006) criteria; secondary end points included cytogenetic responses, hematologic improvement (HI), response duration, survival, and safety. Results Ninety-nine patients were enrolled; the ORR was 32% (17 complete responses [CR] plus 15 marrow CRs [mCRs]), and the overall improvement rate was 51%, which included 18% HI. Similar response rates were observed in all FAB subtypes and IPSS risk categories. Among patients who improved, 82% demonstrated responses by the end of cycle 2. Among 33 patients assessable for a cytogenetic response, 17 (52%) experienced cytogenetic CR (n = 11) or partial response (n = 6). Conclusion Decitabine given on a 5-day schedule provided meaningful clinical benefit for patients with MDS, with more than half demonstrating improvement. This suggests that decitabine can be administered in an outpatient setting with comparable efficacy and safety to the United States Food and Drug Administration–approved inpatient regimen. PMID:19528372

  15. Cardiorespiratory and antinociceptive effects of two different doses of lidocaine administered to horses during a constant intravenous infusion of xylazine and ketamine

    PubMed Central

    2013-01-01

    Background This study investigated the antinociceptive effects of a constant rate infusion (CRI) of lidocaine during xylazine and ketamine anesthesia in horses and aimed to correlate these effects with cardiorespiratory variables, bispectral index (BIS) and plasma lidocaine concentrations. Six adult crossbred mares weighing 320–400 kg were anesthetized on three different occasions. Sedation was performed with xylazine (0.75 mg/kg IV) and anesthetic induction with guaifenesin (75 mg/kg IV) and ketamine (2 mg/kg IV). Anesthesia was maintained with 37.5 μg/kg/min of xylazine and 87.5 μg/kg/min of ketamine both administered intravenously for 75 min. The three treatments consisted of: lidocaine (loading dose: 5 mg/kg, CRI: 100 μg/kg/min; THL); lidocaine (loading dose: 2.5 mg/kg; CRI: 50 μg/kg/min: TLL); and saline (TS); all given 15 min after induction and maintained for 1 h. Antinociception was measured by response to electrical stimulation and bispectral index (BIS) was recorded during anesthesia. Parametric and non-parametric data were compared using ANOVA followed by Student-Newman-Keuls and Friedman tests, respectively. Results Plasma lidocaine concentrations peaked at the end of lidocaine loading dose and was greater in THL (9.61 ± 2.75 μg/mL) vs TLL (4.50 ± 3.34 μg/mL). Electrical noxious stimulation caused purposeful movement in all horses from TS, but no response in THL. The BIS was decreased in THL only and was less when compared to the other treatments throughout anesthesia. Blood pressure, PaO2 and PaCO2 increased and heart rate (HR), respiratory rate (RR), pH, total plasma protein and temperature decreased during anesthesia in all treatments. PaCO2 and HR were greater and RR and pH less in THL compared to TLL and TS at 30 min during anesthesia. All recoveries were considered excellent. Time to standing was longer after THL (60 ± 20 min) than following TLL and TS (32 ± 17 and 30 ± 15 min, respectively

  16. Urinary trimethylselenonium excretion by the rat: effect of level and source of selenium-75

    SciTech Connect

    Nahapetian, A.T.; Janghorbani, M.; Young, V.R.

    1983-02-01

    The purpose of this study was to explore in rats the urinary metabolites of selenium (Se), by using (/sup 75/Se)selenomethionine, (/sup 75/Se)selenocystine, and (/sup 75/Se)selenite, and to assess the effects of low and high levels of Se intake on trimethylselenonium ion (TMSe) excretion in urine. Male adult rats were adapted for 6 weeks to a commercial rat laboratory stock diet (0.25 ppm Se). They were then starved for 24 hours and given an oral dose of either low (16 micrograms Se/kg body weight) or high (1500 micrograms Se/kg body weight) Se as the test Se compounds. Appearance of radioactivity in TMSe and non-TMSe Se metabolites in urine was monitored for 48 hours. About 40% of the /sup 75/Se dose was excreted in urine. TMSe was the major urinary Se metabolite at high, and a minor urinary Se metabolite at low dose levels of Se and for all three Se test compounds. At least 80% of urinary /sup 75/Se and 26-42% of the orally administered /sup 75/Se were excreted as non-TMSe Se metabolites in urine under the latter condition. It is hypothesized that at a requirement intake of Se either a trace or no TMSe is excreted in urine, and it becomes a major excretory metabolite of Se when the dietary trace mineral intake exceeds a requirement level, probably serving as a means of detoxification.

  17. [How large is the tocopherol accumulation capacity of organs? Long term trials with various high oral alpha-tocopherol doses administered to rats and guinea pigs].

    PubMed

    Elmadfa, I; Walter, A

    1981-01-01

    Accumulation of Tocopherol in Various Organs. 1. The influence of different doses of vitamin E on the absorption and accumulation of tocopherol in blood and various organs was studied in long time feeding experiments with male guinea pigs (Pirbright White W 58) and male Sprague Dawley rats. The experiment with guinea pigs lasted 32 weeks, that with rats 46 weeks. Three groups of 20 animals of each species were fed semisynthetic diets containing 0.003 g (Gr. I = control), 0.203 g (Gr. II) and 1.009 g (Gr. III) D, L-alpha-tocopherol acetate per 100 g diet. The ratio of tocopherol contents in the diets was 1:100:500. 2. The tocopherol excretion in the faeces increased significantly according to the vitamin E intake; the absorption rate of tocopherol behaves inversely proportional to the level of supply. 3. The tocopherol concentration in blood serum, liver, heart and adrenals of animals of the Groups II and III increased significantly in comparison with the control animals. The tocopherol accumulation in blood and the analysed organs depends on species and is organ specific: Organs of rats of the control group contain higher levels of alpha-tocopherol compared with those of the corresponding group of guinea pigs. According to the relative accumulation capacity of the organs for vitamin E (I:II:III) following sequences can be considered: Guinea pigs: adrenals and heart, liver, blood; rats: liver, heart, blood, adrenals. 4. The tocopherol accumulating organs are of limited capacity. The ratio of the tocopherol intake (1:100:500) could not be found in any of the analysed organs. PMID:7319728

  18. Sex specific impact of perinatal bisphenol A (BPA) exposure over a range of orally administered doses on rat hypothalamic sexual differentiation

    PubMed Central

    McCaffrey, Katherine A.; Jones, Brian; Mabrey, Natalie; Weiss, Bernard; Swan, Shanna H.; Patisaul, Heather B.

    2013-01-01

    Bisphenol A (BPA) is a high volume production chemical used in polycarbonate plastics, epoxy resins, thermal paper receipts, and other household products. The neural effects of early life BPA exposure, particularly to low doses administered orally, remain unclear. Thus, to better characterize the dose range over which BPA alters sex specific neuroanatomy, we examined the impact of perinatal BPA exposure on two sexually dimorphic regions in the anterior hypothalamus, the sexually dimorphic nucleus of the preoptic area (SDN-POA) and the anterioventral periventricular (AVPV) nucleus. Both are sexually differentiated by estradiol and play a role in sex specific reproductive physiology and behavior. Long Evans rats were prenatally exposed to 10, 100, 1000, 10,000 mg/kg bw/day BPA through daily, noninvasive oral administration of dosed-cookies to the dams. Offspring were reared to adulthood. Their brains were collected and immunolabeled for tyrosine hydroxylase (TH) in the AVPV and calbindin (CALB) in the SDN-POA. We observed decreased TH-ir cell numbers in the female AVPV across all exposure groups, an effect indicative of masculinization. In males, AVPV TH-ir cell numbers were significantly reduced in only the BPA 10 and BPA 10,000 groups. SDN-POA endpoints were unaltered in females but in males SDN-POA volume was significantly lower in all BPA exposure groups. CALB-ir was significantly lower in all but the BPA 1000 group. These effects are consistent with demasculinization. Collectively these data demonstrate that early life oral exposure to BPA at levels well below the current No Observed Adverse Effect Level (NOAEL) of 50 mg/kg/day can alter sex specific hypothalamic morphology in the rat. PMID:23500335

  19. Safety and immunogenicity of two doses of quadrivalent meningococcal conjugate vaccine or one dose of meningococcal group C conjugate vaccine, both administered concomitantly with routine immunization to 12- to 18-month-old children

    PubMed Central

    Noya, Francisco; McCormack, Deirdre; Reynolds, Donna L; Neame, Dion; Oster, Philipp

    2014-01-01

    OBJECTIVES: To describe the immunogenicity and safety of a two-dose series of a quadrivalent meningococcal (serogroups A, C, Y and W) polysaccharide diphtheria toxoid conjugate vaccine (MenACYW-D) administered to toddlers. METHODS: Children were randomly assigned (1:1) at study entry to receive MenACYW-D at 12 and 18 months of age (group 1; n=61) or meningococcal serogroup C conjugate vaccine (MCC) at 12 months of age (group 2; n=62). All received routine childhood immunizations. A, C, Y and W antibody titres were measured in group 1 before and one month after the 18-month MenACYW-D vaccination and were measured in group 2 at one and seven months post-MCC vaccination. Antibodies elicited by diphtheria and tetanus toxoids, and acellular pertussis vaccine adsorbed combined with inactivated poliomyelitis vaccine and Haemophilus influenzae b conjugate (DTaP-IPV-Hib) vaccine coadministered at the 18-month vaccination were measured one month later. Safety data were collected. RESULTS: At 19 months of age, ≥96% in group 1 achieved protective titres for the four meningococcal serogroups after dose 2; 67% in group 2 exhibited protective titres against serogroup C 28 days after MCC vaccination at 12 months of age, declining to 27% seven months later. DTaP-IPV-Hib elicited high antibody concentrations/titres in groups 1 and 2, consistent with historical values. The safety profiles after each dose generated no unexpected safety signals; no serious adverse events were related to vaccination. DISCUSSION: A two-dose series of MenACYW-D given concomitantly with a DTaP-IPV-Hib booster dose at 18 months of age demonstrated a good immunogenicity and safety profile. A two-dose series of MenACYW-D can be used as an alternative to one dose of MCC and provides protection against additional serogroups (NCT ID: NCT01359449). PMID:25285126

  20. Absorption, distribution and excretion of 14C-pilocarpine following oral administration to rats.

    PubMed

    Omori, Yasuhiro; Endo, Takuro; Hara, Yoshiki; Nishiyama, Masahiko; Midgley, Ian; Smart, Clair I; John, Alexandra J; Chasseaud, Leslie F; McBurney, Alan; John, Brian A

    2004-01-01

    The absorption, distribution and excretion of pilocarpine (CAS 92-13-7) were studied after single oral doses of 14C-pilocarpine hydrochloride (CAS 54-71-7) to the Sprague-Dawley rat, administered in aqueous solution mainly at a dose level of 0.3 mg/kg. Rats also received single intravenous doses at 0.3 mg/kg so as to compare 14C pharmacokinetics and excretion. The oral 14C-dose was rapidly and almost completely absorbed from the duodenum and small intestine within 30 min in the male rat and 14C concentrations in plasma declined biexponentially with a terminal half-life of about 9 h. Over the oral dosage range studied, i.e. 0.1-1.0 mg/kg, there was no evidence of significant non-proportionality for Cmax of 14C, whereas there was some such evidence for AUG24. Tissue 14C concentrations in male and pregnant female (Day 18) rats peaked at 0.5 h and mostly declined in parallel with those in the plasma. Excluding tissues concerned with drug absorption and elimination, 14C concentrations in most tissues were similar to, or lower than, those in the plasma. The extent of placental transfer of 14C was small and less than 0.09% of a maternal dose reached a foetus. 14C diffused into maternal milk at concentrations similar to those in the plasma. The 14C-dose was rapidly excreted in male rats, mostly in the urine (about 80%) during 6 h post dose. Recoveries of 14C in mass balance (excretion) studies were in the range 96-100%. There were no apparent gender differences in the disposition of 14C-pilocarpine in the rat. PMID:15112864

  1. Behavioral toxicity and physiological changes from repeated exposure to fluorene administered orally or intraperitoneally to adult male Wistar rats: A dose-response study.

    PubMed

    Peiffer, Julie; Grova, Nathalie; Hidalgo, Sophie; Salquèbre, Guillaume; Rychen, Guido; Bisson, Jean-François; Appenzeller, Brice M R; Schroeder, Henri

    2016-03-01

    Fluorene is one of the most abundant polycyclic aromatic hydrocarbons (PAHs) in the environment by reason of its high volatility. Demonstrated to be a neurotoxicant through inhalation, it was also identified as a contributive PAH to food contamination. Since no data are available on its oral neurotoxicity, the purpose of the present study was to assess the behavioral and physiological toxicity of repeated oral administration of fluorene to adult Wistar male rats. Animals were daily treated with fluorene at 1, 10 or 100mg/kg/day for 28 consecutive days. Administration was intraperitoneal (i.p.) or oral (p.o.) to evaluate the influence of the route of exposure on fluorene toxicity. Following this period of treatment, animals in both groups were subjected to similar cognitive evaluations, namely anxiety (elevated-plus maze), locomotor activity (open-field) and learning and memory abilities (eight-arm maze and avoidance test of an aversive light stimulus), as well as physiological measurements. The behavioral testing occurred from the 28th to the 60th day of the experiment during which fluorene treatment continued uninterrupted. At the end of this period, the concentration levels of fluorene and of three of its monohydroxylated metabolites in blood and brain were determined using a GC-MS/MS method. The results demonstrated a reduction in rat anxiety level at the lowest doses administered (1 and 10mg/kg/day) regardless of the treatment route, whereas locomotor activity and learning abilities remained unchanged. Moreover, a less significant weight gain was noticed in animals i.p.- and p.o.-treated with 100mg/kg/day during the 28-day period of treatment, which, upon comparison with the three other groups, induced a body weight gap that was maintained throughout the experiment. Significant increases in relative liver weight were also observed in a dose-dependent manner in orally treated rats and only in animal treated i.p. with 100mg/kg/day. According to the dose, higher

  2. Determination of designer doping agent--2-ethylamino-1-phenylbutane--in dietary supplements and excretion study following single oral supplement dose.

    PubMed

    Wójtowicz, Marzena; Jarek, Anna; Chajewska, Katarzyna; Turek-Lepa, Ewa; Kwiatkowska, Dorota

    2015-11-10

    The quantitative analysis of a new designer doping agent, 2-ethylamino-1-phenylbutane (EAPB) and its metabolite, 2-amino-1-phenylbutane (APB) in urine samples, and the determination of EAPB in dietary supplement samples, have been presented. The main purpose of the present study was to develop simple and reliable gas chromatography-mass spectrometry method (GC-MS) for excretion study following a single oral administration of dietary supplements containing EAPB. Three analytical methods for the determination of EAPB in urine and supplement samples, and APB in urine samples using the GC-MS system, have been validated. The method of the determination of EAPB in supplement samples was applied to analyze seventeen dietary supplements, CRAZE and DETONATE. Two other methods were used to determine the urinary excretion profile of EAPB and APB in the case of three healthy volunteers and, on further investigation, it was applied to the anti-doping control in sport. Quantification was obtained on the basis of the ions at m/z 86, 58 and 169, monitored for EAPB, APB and diphenylamine (used as an internal standard), respectively. The limits of detection and quantification were 2.4 and 7.3μg/g for EAPB in the case of supplement analysis, 2.9 and 8.8ng/mL for EAPB in the case of urine analysis, and 3.2 and 9.7ng/mL for APB. The other validation parameters as linearity, precision and trueness have been also investigated with the acceptable results. The extraction yield of all presented methods was above 69%. EAPB was detected in fourteen analyzed supplements (not included EAPB in their labels) and its content varied between 1.8 and 16.1mg/g. Following oral administration of three supplements with EAPB to one male and two female volunteers, the parent compound of EAPB and its metabolite were monitored and the excretion parameters as the maximum concentration of the analyte in urine (2.2-4.2μg/mL for EAPB; 1.1-5.1μg/mL for APB) and the time for the maximum height of the excretion

  3. Absorption, tissue distribution, and excretion of tritium-labeled ivermectin in cattle, sheep, and rat

    SciTech Connect

    Chiu, Shuething Lee; Green, M.L.; Baylis, F.P.; Eline, D.; Rosegay, A.; Meriwether, H.; Jacob, T.A. )

    1990-11-01

    Tritium-labeled ivermectin was studied in cattle, sheep, and rat for absorption, tissue residue distribution, and excretion at doses of 0.3 mg/kg of body weight. The drug was absorbed by various dosing routes. By intraruminal and subcutaneous dosing routes, highest tissue residues were present in fat and liver of cattle, with half-lives of 6-8 and 4-5 days, respectively. Shorter half-lives (1-2 days) were observed in sheep and rat. The tissue residue distribution pattern was essentially the same for all species studied and similar in male and female rats. With doses of tritium-labeled avermectin B{sub 1a} ranging from 0.06 to 7.5 mg/kg of body weight, plasma and tissue residue concentrations increased proportionally with the dose. When ivermectin was administered by various routes (ip, sc, iv, oral, and intraruminal), blood residue levels converged to 20-50 ppb 4 h after dosing and then depleted at similar rate regardless of the dosing route. Ivermectin was excreted primarily in the feces, with only less than 2% of the doses being eliminated in the urine in all three species studied.

  4. Species differences in biliary excretion of benzo(a)pyrene

    SciTech Connect

    Weyand, E.H.; Bevan, D.R.

    1986-05-01

    Biliary excretion of benzo(a)pyrene (B(a)P) was investigated in rats, hamsters, and guinea pigs following intratracheal administration. (/sup 3/H)-B(a)P, in amounts of approximately 150 ng or 350 ..mu..g, was instilled into lungs and amounts of radioactivity excreted in bile were monitored for six hrs following administration. Differences in biliary excretion of (/sup 3/H)-B(a)P and/or metabolites among species were observed at low doses but not at high doses. Six hours after instillation of a low dose of B(a)P, 70, 54, and 62% of the dose was excreted in bile of rats, hamsters, and guinea pigs, respectively. Upon administration of the higher dose of B(a)P, approximately 50% of the dose was excreted in bile in six hrs by all species. Thus, rats and guinea pigs exhibit differences in biliary excretion of low and high doses of B(a)P whereas hamsters do not. Profiles of phase II metabolites in rats and hamsters were similar at both low and high doses, with the majority of metabolites being glucuronides and thioether conjugates. However, differences in relative amounts of these conjugates were observed between the two doses, with a shift towards a greater proportion of glucuronides at the higher dose. Metabolites in bile from guinea pigs were primarily thioether conjugates, which accounted for 88% of metabolites at the low dose and 95% at the high dose.

  5. Urinary trimethylselenonium excretion by the rat: effect of level and source of /sup 75/Se

    SciTech Connect

    Nahapetian, A.T.; Janghorbani, M.; Young, V.R.

    1983-02-01

    The purpose of this study was to explore in rats the urinary metabolites of selenium (Se), by using (/sup 75/Se)selenomethionine, (/sup 75/Se)selenocystine, and (/sup 75/Se)selenite, and to assess the effects of low and high levels of Se intake on trimethylselenonium ion (TMSe) excretion in urine. Male adult rats were adapted for 6 weeks to a commercial rat laboratory stock diet (0.25 ppm Se). They were then starved for 24 hours and given an oral dose of either low (16 micrograms Se/kg body weight) or high (1500 micrograms Se/kg body weight) Se as the test Se compounds. Appearance of radioactivity in TMSe and non-TMSe Se metabolites in urine was monitored for 48 hours. About 40% of the /sup 75/Se dose was excreted in urine. TMSe was the major urinary Se metabolite (57-69% of urinary /sup 75/Se and 16-25% of oral /sup 75/Se dose) at high, and a minor urinary Se metabolite (10% of urinary /sup 75/Se and 3-4% of oral /sup 75/Se dose) at low dose levels of Se and for all three Se test compounds. At least 80% of urinary /sup 75/Se and 26-42% of the orally administered /sup 75/Se were excreted as non-TMSe Se metabolites in urine under the latter condition. It is hypothesized that at a requirement intake of Se either a trace or no TMSe is excreted in urine, and it becomes a major excretory metabolite of Se when the dietary trace mineral intake exceeds a requirement level, probably serving as a means of detoxification.

  6. Relating Doses of Contrast Agent Administered to TIC and Semi-Quantitative Parameters on DCE-MRI: Based on a Murine Breast Tumor Model

    PubMed Central

    Zhang, Qi; Guo, Qi; Zhao, Feixiang; Li, Tongwei; Zhang, Xuening

    2016-01-01

    Objective To explore the changes in the time-signal intensity curve(TIC) type and semi-quantitative parameters of dynamic contrast-enhanced(DCE)imaging in relation to variations in the contrast agent(CA) dosage in the Walker 256 murine breast tumor model, and to determine the appropriate parameters for the evaluation ofneoadjuvantchemotherapy(NAC)response. Materials and Methods Walker 256 breast tumor models were established in 21 rats, which were randomly divided into three groups of7rats each. Routine scanning and DCE-magnetic resonance imaging (MRI) of the rats were performed using a 7T MR scanner. The three groups of rats were administered different dosages of the CA0.2mmol/kg, 0.3mmol/kg, and 0.5mmol/kg, respectively; and the corresponding TICs the semi-quantitative parameters were calculated and compared among the three groups. Results The TICs were not influenced by the CA dosage and presented a washout pattern in all of the tumors evaluated and weren’t influenced by the CA dose. The values of the initial enhancement percentage(Efirst), initial enhancement velocity(Vfirst), maximum signal(Smax), maximum enhancement percentage(Emax), washout percentage(Ewash), and signal enhancement ratio(SER) showed statistically significant differences among the three groups (F = 16.952, p = 0.001; F = 69.483, p<0.001; F = 54.838, p<0.001; F = 12.510, p = 0.003; F = 5.248, p = 0.031; F = 9.733, p = 0.006, respectively). However, the values of the time to peak(Tpeak), maximum enhancement velocity(Vmax), and washout velocity(Vwash)did not differ significantly among the three dosage groups (F = 0.065, p = 0.937; F = 1.505, p = 0.273; χ2 = 1.423, p = 0.319, respectively); the washout slope(Slopewash), too, was uninfluenced by the dosage(F = 1.654, p = 0.244). Conclusion The CA dosage didn’t affect the TIC type, Tpeak, Vmax, Vwash or Slopewash. These dose-independent parameters as well as the TIC type might be more useful for monitoring the NAC response because they allow

  7. Rat hepatocarcinogenesis induced by N-nitrosodiethylamine and N-nitrosomorpholine continuously administered at low doses. From basophilic areas of hepatocytes to hepatocellular tumors.

    PubMed Central

    Cortinovis, C.; Klimek, F.; Nogueira, E.

    1991-01-01

    The development of hepatocellular tumors was investigated with histological, histochemical, and morphometrical methods in male Sprague-Dawley rats continuously administered N-nitrosodiethylamine (DEN) or N-nitrosomorpholine (NNM) in the drinking water at low doses (0.5 mg DEN/100 ml; 1 mg NNM/100 ml). Groups of control, DEN-, and NNM-treated rats were investigated at 5-week intervals. Similar results were obtained in DEN- and NNM-treated rats. Two types of areas composed of basophilic or glycogenotic hepatocytes were observed preceding the appearance of hepatocellular adenomas and carcinomas. Besides their cytologic differences, the basophilic and glycogenotic areas induced displayed distinct histochemical features. Both types of areas were detected simultaneously and increased in parallel with time to a similar incidence, but basophilic areas reached larger sizes than the glycogenotic ones. Furthermore, each type of area, which clustered around and along efferent veins, was differently linked to tumorigenesis. Basophilic areas frequently developed into basophilic adenomas and trabecular carcinomas through a characteristic sequence. Early basophilic areas consisted of hepatocytes with lamellar cytoplasmic hyperbasophilia and exhibited the normal laminar liver structure. With time, an increasing number of basophilic areas also contained hepatocytes with powdered diffuse hyperbasophilia, which frequently were arranged in thick trabeculae, showed abundant mitotic figures, and invaded efferent veins. Neither such signs of malignancy nor conversion into basophilic areas or tumors could be established for areas of clear and acidophilic glycogenotic hepatocytes. However, a few small glycogenotic adenomas probably developed from glycogenotic areas. Our data thus underline the central role of basophilic areas for hepatocarcinogenesis. Moreover, taking into account the data from other experiments, it seems likely that although glycogenotic areas may be associated with the

  8. The effect of phenobarbital on the metabolism and excretion of thyroxine in rats

    SciTech Connect

    McClain, R.M.; Levin, A.A.; Posch, R.; Downing, J.C.

    1989-06-15

    The effect of phenobarbital on thyroid function and the metabolism and biliary excretion of thyroxine in rats was determined. Phenobarbital, administered for 2 weeks at a dose of 100 mg/kg/day, resulted in an increase in hepatic and thyroid gland weights, decreased circulating levels of T4, T3 and rT3, and increased TSH levels in male and female rats. After 3 months of treatment liver and thyroid weights were still increased; however, hormone values were not as markedly affected indicating that the rats had partially compensated for the effect on thyroid function. In thyroidectomized rats the plasma clearance of thyroxine was increased with phenobarbital. In bile duct cannulated phenobarbital-treated male rats the hepatic uptake at 4 hr was markedly increased. Bile flow was increased and the 4-hr cumulative biliary excretion of administered radioactivity was increased by 42%. Most of the increase in the excretion (76%) was accounted for by an increase in the excretion of thyroxine-glucuronide in phenobarbital-treated rats. Hepatic thyroxine-glucuronyltransferase activity in phenobarbital-treated rats expressed as picomoles per milligram of protein was increased by 40%; enzyme activity per gram of liver was increased by about twofold which, coupled with increased hepatic weight, resulted in about a threefold increase in total hepatic thyroxine-glucuronyltransferase activity in phenobarbital-treated rats as compared to that of controls. Qualitatively similar effects on metabolism, excretion, and enzyme induction were noted in female rats; however, the magnitude of increase was less than that observed in male rats. It is concluded that the effect of phenobarbital on thyroid function in rats is primarily a result of its effects on the hepatic disposition of thyroid hormone.

  9. Single-Dose Pharmacokinetics and Safety of Abacavir (1592U89), Zidovudine, and Lamivudine Administered Alone and in Combination in Adults with Human Immunodeficiency Virus Infection

    PubMed Central

    Wang, Laurene H.; Chittick, Gregory E.; McDowell, James A.

    1999-01-01

    Abacavir (1592U89), a nucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type-1 (HIV-1), has been evaluated for efficacy and safety in combination regimens with other nucleoside analogs, including zidovudine (ZDV) and lamivudine (3TC). To evaluate the potential pharmacokinetic interactions between these agents, 15 HIV-1-infected adults with a median CD4+ cell count of 347 cells/mm3 (range, 238 to 570 cells/mm3) were enrolled in a randomized, seven-period crossover study. The pharmacokinetics and safety of single doses of abacavir (600 mg), ZDV (300 mg), and 3TC (150 mg) were evaluated when each drug was given alone or when any two or three drugs were given concurrently. The concentrations of all drugs in plasma and the concentrations of ZDV and its 5′-glucuronide metabolite, GZDV, in urine were measured for up to 24 h postdosing, and pharmacokinetic parameter values were calculated by noncompartmental methods. The maximum drug concentration (Cmax), the area under the concentration-time curve from time zero to infinity (AUC0–∞), time to Cmax (Tmax), and apparent elimination half-life (t1/2) of abacavir in plasma were unaffected by coadministration with ZDV and/or 3TC. Coadministration of abacavir with ZDV (with or without 3TC) decreased the mean Cmax of ZDV by approximately 20% (from 1.5 to 1.2 μg/ml), delayed the median Tmax for ZDV by 0.5 h, increased the mean AUC0–∞ for GZDV by up to 40% (from 11.8 to 16.5 μg · h/ml), and delayed the median Tmax for GZDV by approximately 0.5 h. Coadministration of abacavir with 3TC (with or without ZDV) decreased the mean AUC0–∞ for 3TC by approximately 15% (from 5.1 to 4.3 μg · h/ml), decreased the mean Cmax by approximately 35% (from 1.4 to 0.9 μg/ml), and delayed the median Tmax by approximately 1 h. While these changes were statistically significant, they are similar to the effect of food intake (for ZDV) or affect an inactive metabolite (for GZDV) or are

  10. KAE609 (Cipargamin), a New Spiroindolone Agent for the Treatment of Malaria: Evaluation of the Absorption, Distribution, Metabolism, and Excretion of a Single Oral 300-mg Dose of [14C]KAE609 in Healthy Male Subjects.

    PubMed

    Huskey, Su-Er W; Zhu, Chun-Qi; Fredenhagen, Andreas; Kühnöl, Jürgen; Luneau, Alexandre; Jian, Zhigang; Yang, Ziping; Miao, Zhuang; Yang, Fan; Jain, Jay P; Sunkara, Gangadhar; Mangold, James B; Stein, Daniel S

    2016-05-01

    KAE609 [(1'R,3'S)-5,7'-dichloro-6'-fluoro-3'-methyl-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyridol[3,4-b]indol]-2-one] is a potent, fast-acting, schizonticidal agent in clinical development for the treatment of malaria. This study investigated the absorption, distribution, metabolism, and excretion of KAE609 after oral administration of [(14)C]KAE609 in healthy subjects. After oral administration to human subjects, KAE609 was the major radioactive component (approximately 76% of the total radioactivity in plasma); M23 was the major circulating oxidative metabolite (approximately 12% of the total radioactivity in plasma). Several minor oxidative metabolites (M14, M16, M18, and M23.5B) were also identified, each accounting for approximately 3%-8% of the total radioactivity in plasma. KAE609 was well absorbed and extensively metabolized, such that KAE609 accounted for approximately 32% of the dose in feces. The elimination of KAE609 and metabolites was primarily mediated via biliary pathways. M23 was the major metabolite in feces. Subjects reported semen discoloration after dosing in prior studies; therefore, semen samples were collected once from each subject to further evaluate this clinical observation. Radioactivity excreted in semen was negligible, but the major component in semen was M23, supporting the rationale that this yellow-colored metabolite was the main source of semen discoloration. In this study, a new metabolite, M16, was identified in all biologic matrices albeit at low levels. All 19 recombinant human cytochrome P450 enzymes were capable of catalyzing the hydroxylation of M23 to form M16 even though the extent of turnover was very low. Thus, electrochemistry was used to generate a sufficient quantity of M16 for structural elucidation. Metabolic pathways of KAE609 in humans are summarized herein and M23 is the major metabolite in plasma and excreta. PMID:26921387

  11. Pharmacokinetics of oral 6-mercaptopurine: relationship between plasma levels and urine excretion of parent drug.

    PubMed

    Endresen, L; Lie, S O; Storm-Mathisen, I; Rugstad, H E; Stokke, O

    1990-05-01

    Plasma levels and cumulative urine excretion of 6-mercaptopurine (6-MP) were measured using a specific and sensitive high-performance liquid chromatographic assay in seven children with acute lymphoblastic leukemia (ALL) as well as in one healthy volunteer. The dose of 6-MP varied in the range of 25-75 mg/m2 of body surface area and was administered with a standard breakfast. A 4- to 11-fold variation between individuals was found in the pharmacokinetic parameters: peak concentration, time to reach peak, area under the plasma concentration-time curve (AUC), and fraction of dose excreted in the urine. Three repeated determinations in one individual revealed that AUC also varied more than sixfold following an overnight fast. In three individuals, the reducing agents glutathione (10 mg/kg) and ascorbic acid (15 mg/kg) were coadministered with 6-MP to evaluate their possible role in the protection of 6-MP from oxidation and degradation in the intestinal lumen. No consistent effect was observed, however, on the AUCs of either of these agents. A clear relationship was found between AUCs and the 24-h urinary excretion of unchanged drug (r = 0.9381), indicating that determinations of 6-MP in the urine may replace the painful procedure of repeated blood sampling. Further studies are necessary to determine the factors contributing to the unpredictable plasma levels following oral doses of 6-MP and to determine the value of pharmacokinetic monitoring in ALL patients. PMID:2349605

  12. Safety, tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor AZD5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours

    PubMed Central

    Boss, D. S.; Schwartz, G. K.; Middleton, M. R.; Amakye, D. D.; Swaisland, H.; Midgley, R. S.; Ranson, M.; Danson, S.; Calvert, H.; Plummer, R.; Morris, C.; Carvajal, R. D.; Chirieac, L. R.; Schellens, J. H. M.; Shapiro, G. I.

    2010-01-01

    Background: AZD5438 is an orally bioavailable inhibitor of cyclin E-cdk2, cyclin A-cdk2 and cyclin B-cdk1 complexes. Three phase I studies assessed the clinical safety, tolerability, pharmacokinetics and pharmacodynamics of AZD5438 when administered in different dosing schedules. Patients and methods: AZD5438 was administered four times daily, once every 7 days (study 1), for 14 consecutive days followed by 7 days of rest (study 2), or continuously (study 3), to patients with advanced solid tumours. Dose escalation proceeded until the emergence of dose-limiting toxic effects. Results: Sixty-four patients were included across the three studies (19, 17 and 28, respectively). Nausea and vomiting were the most common adverse events. When dosed continuously, 40 mg four times daily was considered intolerable, and due to safety issues, all studies were terminated prematurely. Consequently, no intolerable dose was identified during the weekly schedule. Pharmacokinetics demonstrated dose-proportional exposure, high interpatient variability and accumulation after multiple doses. Skin biopsies indicated reduced retinoblastoma protein phosphorylation at cdk2 phospho-sites; other pharmacodynamic assessments did not reveal consistent trends. Conclusions: AZD5438 was generally well tolerated in a weekly dosing schedule, but not in continuous schedules. The clinical development programme for AZD5438 was discontinued owing to tolerability and exposure data from these studies. PMID:19825886

  13. NTP Toxicity Studies of Sodium Cyanide (CAS No. 143-33-9) Administered by Dosed Water to F344/N Rats and B6C3F1 Mice.

    PubMed

    1993-11-01

    Cyanide and its salts are used extensively in industry and manufacturing and are found in water and food consumed by humans. Chronic exposure to low levels of cyanide is suspected to be responsible for various neuropathic and thyrotoxic conditions in humans. Data in the literature indicate that long-term exposure to near-lethal concentrations of cyanide may produce lesions in rodents similar to those linked to chronic cyanide exposure in humans. However, few data are available on the effects of subchronic exposure to cyanide concentrations that are not acutely toxic. To address this lack of data, 13-week toxicity studies on cyanide were conducted with male and female F344/N rats and B6C3F1 mice administered low doses of sodium cyanide in drinking water. Animals were evaluated for histopathology, clinical chemistry, hematology, urine chemistry, and reproductive toxicity. In addition, the mutagenicity of sodium cyanide was assessed in Salmonella typhimurium. Groups of 10 rats and 10 mice per sex were administered sodium cyanide in drinking water at concentrations of 0, 3, 10, 30, 100, and 300 ppm for 13 weeks. No deaths attributed to sodium cyanide administration occurred in either species. In animals exposed to 300 ppm, male rats had slightly lower final mean body weights and mean body weight gains and female mice had slightly lower final mean body weights than the respective controls. Water consumption by rats and mice in the 100 and 300 ppm groups was 10% to 30% lower than that by the controls; however, no clinical signs attributable to sodium cyanide administration or to dehydration were observed. No gross or microscopic changes specifically related to cyanide toxicity occurred at any site in males or females of either species. In particular, no lesions were found in the brain or thyroid gland. Differences between absolute and relative organ weights of exposed and control animals were minor and sporadic and were not exposure concentration dependent; these

  14. Excretion of Morroniside in Rat Urine After Single Oral and Intravenous Administration.

    PubMed

    Xiong, Shan; Li, Jinglai; Zhang, Zhenqing

    2016-07-01

    This study was designed to develop a sensitive, simple and rapid method for the quantitation of morroniside in rat urine using high-performance liquid chromatography-tandem mass spectrometry (LC-MS-MS) and to investigate the excretion of morroniside in rat urine. The mobile phase consisted of water-acetonitrile (gradient elution) at a flow rate of 0.4 mL/min. Detection was performed using positive-ion electrospray ionization in multiple reaction monitoring (MRM) modes. And the detection of morroniside in rat urine by the LC-MS-MS was accurate and precise from 1.0 to 2,500 ng/mL (a correlation coefficient of 0.9953). The recoveries and matrix effects were all in line with the biological sample measurement requirements. The intraday accuracy was 88.68-105.78% with precision of 6.50-11.19% and the interday accuracy was 95.77-102.43% with precision of 7.08-10.40%. Excretion data of morroniside in rat urine indicated that 21.43‰ (i.g.) and 100.35% (i.v.) of the dose administered was excreted as unconverted form, respectively. And the maximal excretion rate was 27.57 and 482.42 μg/h after oral and intravenous administration, respectively. These results indicated that the developed method has satisfactory sensitivity, accuracy and precision for the quantification of morroniside in rat urine. PMID:26896349

  15. Pharmacokinetics and Safety of FV-100, a Novel Oral Anti-Herpes Zoster Nucleoside Analogue, Administered in Single and Multiple Doses to Healthy Young Adult and Elderly Adult Volunteers▿

    PubMed Central

    Pentikis, Helen S.; Matson, Mark; Atiee, George; Boehlecke, Brian; Hutchins, Jeff T.; Patti, Joseph M.; Henson, Geoffrey W.; Morris, Amy

    2011-01-01

    FV-100 is the prodrug of the highly potent anti-varicella zoster virus bicyclic nucleoside analogue CF-1743. To characterize the pharmacokinetics and safety of oral FV-100, 3 randomized, double-blind, placebo-controlled clinical trials were conducted: (i) a single-ascending-dose study in 32 healthy subjects aged 18 to 55 years (100-, 200-, 400-, and 800-mg doses) with an evaluation of the food effect in the 400-mg group; (ii) a multiple-ascending-dose study in 48 subjects aged 18 to 55 years (100 mg once daily [QD], 200 mg QD, 400 mg QD, 400 mg twice a day, and 800 mg QD for 7 days); and (iii) a 2-part study in subjects aged 65 years and older with a single 400-mg dose in 15 subjects and a 400-mg QD dosing regimen for 7 days in 12 subjects. FV-100 was rapidly and extensively converted to CF-1743, the concentration of which remained above that required to reduce viral activity by 50% for the 24-hour dosing period. Renal excretion of CF-1743 was very low. A high-fat meal reduced exposure to CF-1743; a low-fat meal did not. Pharmacokinetic parameters for the elderly subjects were comparable to those for the younger subjects. FV-100 was well tolerated by all subjects. The pharmacokinetic and safety profiles of FV-100 support its continued investigation for the treatment of herpes zoster and prevention of postherpetic neuralgia with once-daily dosing and without dose modifications for elderly or renally impaired patients. PMID:21444712

  16. Pharmacokinetics, tissue distribution, and excretion of nomegestrol acetate in female rats.

    PubMed

    Huang, Qingbiao; Chen, Xiaoke; Zhu, Yan; Cao, Lin; Riviere, Jim E

    2015-12-01

    Nomegestrol acetate (NOMAC), a synthetic progestogen derived from 19-norprogesterone, is an orally active drug with a strong affinity for the progesterone receptor. NOMAC inhibits ovulation and is devoid of undesirable androgenic and estrogenic activities. The aim of this study was to evaluate the pharmacokinetics, tissue distribution, and excretion of NOMAC in female rats. Sprague-Dawley female rats were orally administered a single dose of NOMAC (10, 20 or 40 mg/kg) and drug plasma concentrations at different times were determined by RP-HPLC. Tissue distribution at 1, 2, and 4 h and excretion of NOMAC into bile, urine, and feces after dosing were investigated. The results showed that NOMAC was rapidly absorbed after oral administration, with [Formula: see text] of 1-2 h. The plasma concentration-time curves were fitted in a two-compartment model. The exposure to NOMAC ([Formula: see text] and [Formula: see text]) increased dose proportionally from 10 to 40 mg/kg. The average CL and [Formula: see text] were 5.58 L/(h·kg) and 10.8 h, respectively. The highest concentrations of NOMAC in ovary, liver, kidney, lung, heart, brain, spleen, muscle, and uterus were observed at 2 h, whereas the highest concentrations in stomach, pituitary, and hypothalamus appeared at 1 h. The total cumulative excretion of NOMAC in feces (0-72 h), urine (0-72 h), and bile (0-48 h) was ~1.06, 0.03, and 0.08 % of the oral administered dose, respectively. This study indicated that NOMAC had a widespread distribution in tissues, including ovary, pituitary, and hypothalamus, which are main target tissues where NOMAC inhibits ovulation. NOMAC was excreted via both feces and urine with few unchanged NOMAC excreted. Enterohepatic circulation was found in the drug elimination; however, it did not significantly affect [Formula: see text]. PMID:25168884

  17. Excretion of malondialdehyde, formaldehyde, acetaldehyde and acetone in the urine of rats following acute and chronic administration of ethanol.

    PubMed

    Moser, J; Bagchi, D; Akubue, P I; Stohs, S J

    1993-05-01

    Recent studies have shown that xenobiotics which induce oxidative stress result in an increased production and excretion of acetaldehyde (ACT), formaldehyde (FA), acetone (ACON) and malondialdehyde (MDA) in the urine of rats. We have therefore examined the effect of acute and chronic ethanol administration on the excretion of these four lipid metabolites in female Sprague-Dawley rats. Urine samples were collected over dry ice for 6 hr time periods. Aliquots of urine were derivatized with 2,4-dinitrophenylhydrazine HCl, and extracted with n-pentane. High pressure lipid chromatogrpahy (HPLC) was used to quantitate and the hydrazones of the four lipid metabolite products. Following a single, oral, acute dose of 5 g ethanol/kg, urinary excretion of ACT increased approximately 5.8-fold from 6 to 12 hr posttreatment, and decreased thereafter. FA excretion decreased by approximately 50% from 0 to 12 hr, returned to control values in the 18-24 hr urine samples, and was 1.3-fold greater than control values at 42-48 hr. ACON increased 3.1-fold over control values from 0 to 30 hr and remained elevated throughout the remaining 18 hr of the study. The excretion of MDA increased approximately 1.5-fold from 18 to 36 hr, then remained constant through the 48 hr time point. In a separate series of experiments, a chronic oral dose of 0.5 g ethanol/kg was administered to rats for 10 consecutive days and the urinary excretion of the lipid metabolites MDA, FA, ACT and ACON was examined for 11 days, beginning with the first day of ethanol administration.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8352840

  18. Estimation of benchmark dose as the threshold levels of urinary cadmium, based on excretion of total protein, {beta} {sub 2}-microglobulin, and N-acetyl-{beta}-D-glucosaminidase in cadmium nonpolluted regions in Japan

    SciTech Connect

    Kobayashi, Etsuko . E-mail: ekoba@faculty.chiba-u.jp; Suwazono, Yasushi; Uetani, Mirei; Inaba, Takeya; Oishi, Mitsuhiro; Kido, Teruhiko; Nishijo, Muneko; Nakagawa, Hideaki; Nogawa, Koji

    2006-07-15

    Previously, we investigated the association between urinary cadmium (Cd) concentration and indicators of renal dysfunction, including total protein, {beta} {sub 2}-microglobulin ({beta} {sub 2}-MG), and N-acetyl-{beta}-D-glucosaminidase (NAG). In 2778 inhabitants {>=}50 years of age (1114 men, 1664 women) in three different Cd nonpolluted areas in Japan, we showed that a dose-response relationship existed between renal effects and Cd exposure in the general environment without any known Cd pollution. However, we could not estimate the threshold levels of urinary Cd at that time. In the present study, we estimated the threshold levels of urinary Cd as the benchmark dose low (BMDL) using the benchmark dose (BMD) approach. Urinary Cd excretion was divided into 10 categories, and an abnormality rate was calculated for each. Cut-off values for urinary substances were defined as corresponding to the 84% and 95% upper limit values of the target population who have not smoked. Then we calculated the BMD and BMDL using a log-logistic model. The values of BMD and BMDL for all urinary substances could be calculated. The BMDL for the 84% cut-off value of {beta} {sub 2}-MG, setting an abnormal value at 5%, was 2.4 {mu}g/g creatinine (cr) in men and 3.3 {mu}g/g cr in women. In conclusion, the present study demonstrated that the threshold level of urinary Cd could be estimated in people living in the general environment without any known Cd-pollution in Japan, and the value was inferred to be almost the same as that in Belgium, Sweden, and China.

  19. Excretion of Δ9-Tetrahydrocannabinol in Sweat

    PubMed Central

    Huestis, Marilyn A.; Scheidweiler, Karl B.; Saito, Takeshi; Fortner, Neil; Abraham, Tsadik; Gustafson, Richard A.; Smith, Michael L.

    2008-01-01

    Sweat testing is a noninvasive technique for monitoring drug exposure over a 7-day period in treatment, criminal justice, and employment settings. We evaluated Δ9-tetrahydrocannabinol (THC) excretion in 11 daily cannabis users after cessation of drug use. PharmChek® sweat patches worn for 7 days were analyzed for THC by gas chromatography-mass spectrometry (GC/MS). The limit of quantification (LOQ) for the method was 0.4 ng THC/patch. Sweat patches worn the first week of continuously monitored abstinence had THC above the United States Substance Abuse Mental Health Services Administration’s proposed cutoff concentration for federal workplace testing of 1 ng THC/patch. Mean ± S.E.M. THC concentrations were 3.85 ± 0.86 ng THC/patch. Eight of 11 subjects had negative patches the second week and one produced THC positive patches for four weeks of monitored abstinence. We also tested daily and weekly sweat patches from 7 subjects who were administered oral doses of up to 14.8 mg THC/day for five consecutive days. In this oral THC administration study, no daily or weekly patches had THC above the LOQ; concurrent plasma THC concentrations were all less than 6.1 μg/L. In conclusion, using proposed federal cutoff concentrations, most daily cannabis users will have a positive sweat patch in the first week after ceasing drug use and a negative patch after subsequent weeks, although patches may remain positive for four weeks or more. Oral ingestion of up to 14.8 mg THC daily does not produce a THC positive sweat patch test. PMID:17481836

  20. Effects of Rate of Infusion and Probenecid on Serum Levels, Renal Excretion, and Tolerance of Intravenous Doses of Cefoxitin in Humans: Comparison with Cephalothin

    PubMed Central

    Goodwin, C. Stewart; Raftery, E. B.; Goldberg, A. D.; Skeggs, H.; Till, A. E.; Martin, C. M.

    1974-01-01

    Using a randomized crossover design, 1-g intravenous doses of cephalothin and cefoxitin, a cephalosporinase-resistant cephamycin, were infused into 12 normal adult males over periods of 120, 30, and 3 min, the last with and without prior intravenous infusions of probenecid (1 g). Mean peak serum concentrations of antibiotic activity after cephalothin infusions were 23, 56, 103, and 102 μg/ml, respectively, and after cefoxitin infusions they were 27, 74, 115, and 125 μg/ml, respectively. Probenecid treatment prolonged the terminal serum half-life of cephalothin-like activity from 0.52 to 1.0 h, and of cefoxitin from 0.68 to 1.4 h. In contrast to cephalothin, which was found to be metabolized about 25% to the less active desacetyl form, cefoxitin was metabolized less than 2% to the virtually inactive descarbamyl form, as judged from urinary recoveries. Neither antibiotic displayed detectable organ toxicity. Of 300 recent clinical isolates of gram-negative bacilli other than Pseudomonas spp., 83% were susceptible to cephalothin but 95% were susceptible to cefoxitin. Organisms resistant to cephalothin but susceptible to cefoxitin included strains of Escherichia coli, Proteus vulgaris, Klebsiella spp., Serratia marcescens, Enterobacter spp., and Bacteroides spp. PMID:15830485

  1. Long-Term Safety and Immunogenicity of a Tetravalent Live-Attenuated Dengue Vaccine and Evaluation of a Booster Dose Administered to Healthy Thai Children

    PubMed Central

    Watanaveeradej, Veerachai; Simasathien, Sriluck; Mammen, Mammen P.; Nisalak, Ananda; Tournay, Elodie; Kerdpanich, Phirangkul; Samakoses, Rudiwilai; Putnak, Robert J.; Gibbons, Robert V.; Yoon, In-Kyu; Jarman, Richard G.; De La Barrera, Rafael; Moris, Philippe; Eckels, Kenneth H.; Thomas, Stephen J.; Innis, Bruce L.

    2016-01-01

    We evaluated the safety and immunogenicity of two doses of a live-attenuated, tetravalent dengue virus vaccine (F17/Pre formulation) and a booster dose in a dengue endemic setting in two studies. Seven children (7- to 8-year-olds) were followed for 1 year after dose 2 and then given a booster dose (F17/Pre formulation), and followed for four more years (Child study). In the Infant study, 49 2-year-olds, vaccinated as infants, were followed for approximately 3.5 years after dose 2 and then given a booster dose (F17) and followed for one additional year. Two clinically notable events were observed, both in dengue vaccine recipients in the Infant study: 1 case of dengue approximately 2.7 years after dose 2 and 1 case of suspected dengue after booster vaccinations. The booster vaccinations had a favorable safety profile in terms of reactogenicity and adverse events reported during the 1-month follow-up periods. No vaccine-related serious adverse events were reported during the studies. Neutralizing antibodies against dengue viruses 1–4 waned during the 1–3 years before boosting, which elicited a short-lived booster response but did not provide a long-lived, multivalent antibody response in most subjects. Overall, this candidate vaccine did not elicit a durable humoral immune response. PMID:27022153

  2. Long-Term Safety and Immunogenicity of a Tetravalent Live-Attenuated Dengue Vaccine and Evaluation of a Booster Dose Administered to Healthy Thai Children.

    PubMed

    Watanaveeradej, Veerachai; Simasathien, Sriluck; Mammen, Mammen P; Nisalak, Ananda; Tournay, Elodie; Kerdpanich, Phirangkul; Samakoses, Rudiwilai; Putnak, Robert J; Gibbons, Robert V; Yoon, In-Kyu; Jarman, Richard G; De La Barrera, Rafael; Moris, Philippe; Eckels, Kenneth H; Thomas, Stephen J; Innis, Bruce L

    2016-06-01

    We evaluated the safety and immunogenicity of two doses of a live-attenuated, tetravalent dengue virus vaccine (F17/Pre formulation) and a booster dose in a dengue endemic setting in two studies. Seven children (7- to 8-year-olds) were followed for 1 year after dose 2 and then given a booster dose (F17/Pre formulation), and followed for four more years (Child study). In the Infant study, 49 2-year-olds, vaccinated as infants, were followed for approximately 3.5 years after dose 2 and then given a booster dose (F17) and followed for one additional year. Two clinically notable events were observed, both in dengue vaccine recipients in the Infant study: 1 case of dengue approximately 2.7 years after dose 2 and 1 case of suspected dengue after booster vaccinations. The booster vaccinations had a favorable safety profile in terms of reactogenicity and adverse events reported during the 1-month follow-up periods. No vaccine-related serious adverse events were reported during the studies. Neutralizing antibodies against dengue viruses 1-4 waned during the 1-3 years before boosting, which elicited a short-lived booster response but did not provide a long-lived, multivalent antibody response in most subjects. Overall, this candidate vaccine did not elicit a durable humoral immune response. PMID:27022153

  3. 21 CFR 320.27 - Guidelines on the design of a multiple-dose in vivo bioavailability study.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... a drug product in the following circumstances: (i) There is a difference in the rate of absorption but not in the extent of absorption. (ii) There is excessive variability in bioavailability from... excretion rate during the absorption and elimination phases of a single dose administered at steady-state...

  4. Phase I dose-escalation and pharmacokinetic study of ispinesib, a kinesin spindle protein inhibitor, administered on days 1 and 15 of a 28-day schedule in patients with no prior treatment for advanced breast cancer.

    PubMed

    Gomez, Henry L; Philco, Manuel; Pimentel, Patricia; Kiyan, Miriam; Monsalvo, Maria Laura; Conlan, Maureen G; Saikali, Khalil G; Chen, Michael M; Seroogy, Joseph J; Wolff, Andrew A; Escandon, Rafael D

    2012-03-01

    The objective of the study was to evaluate the safety, pharmacokinetics, and antitumor activity of ispinesib, a kinesin spindle protein inhibitor. Patients with locally advanced or metastatic breast cancer who had received only prior neoadjuvant or adjuvant chemotherapy were treated with escalating doses of ispinesib administered as a 1-h infusion on days 1 and 15 every 28 days until toxicity or progression of disease. Doses were escalated until dose-limiting toxicity was observed in two out of six patients during cycle 1. A total of 16 patients were treated at three dose levels: 10 mg/m (n=3), 12 mg/m (n=6), and 14 mg/m (n=7). Forty-four percent of the patients had locally advanced disease and 56% had metastatic disease; 50% were estrogen receptor positive, 44% were progesterone receptor positive, 25% human epidermal growth factor 2 were positive, and 31% triple (estrogen receptor, progesterone receptor, human epidermal growth factor 2) negative. Sixty-nine percent of patients were chemo-naive. The maximum tolerated dose was 12 mg/m and dose-limiting toxicity was grade 3 increased aspartate aminotransferase and alanine aminotransferase. The most common toxicities included neutropenia (88%; 38% grade 3 and 44% grade 4), increased alanine aminotransferase (56%), anemia (38%), increased aspartate aminotransferase (31%), and diarrhea (31%). No neuropathy, mucositis, or alopecia was reported. Among the 15 patients evaluable for antitumor activity, there were three partial responses, one confirmed by the response evaluation criteria in solid tumors (7% response rate). Nine patients (60%) had stable disease lasting at least 42 days, with four (27%) lasting for at least 90 days. Disease stabilization (partial responses+stable disease) was observed in 11 (73.3%) patients. In conclusion, ispinesib was well tolerated when administered on days 1 and 15 every 28 days. Limited activity was observed with this schedule in patients with previously untreated advanced breast cancer

  5. Patient biodistribution of intraperitoneally administered yttrium-90-labeled antibody.

    PubMed

    Hnatowich, D J; Chinol, M; Siebecker, D A; Gionet, M; Griffin, T; Doherty, P W; Hunter, R; Kase, K R

    1988-08-01

    Although 90Y is one of the best radionuclides for radioimmunotherapeutic applications, the lack of gamma rays in its decay complicates the estimation of radiation dose since its biodistribution cannot be accurately determined by external imaging. A limited clinical trial has been conducted with tracer doses (1 mCi) of 90Y in five patients who then received second-look surgery such that tissue samples were obtained for accurate radioactivity quantitation by in vitro counting. The anti-ovarian antibody OC-125 as the F(ab')2 fragment was coupled with diethylenetriaminepentaacetic acid, radiolabeled with 90Y and administered intraperitoneally to patients with suspected or documented ovarian cancer. Size exclusion and ion exchange high performance liquid chromatography analysis of patient ascitic fluid and serum samples showed no evidence of radiolabel instability although a high molecular weight species (presumably immune complex) was observed in three patients. Total urinary excretion of radioactivity prior to surgery averaged 7% of the administered radioactivity while at surgery the mean organ accumulation was 8% of the administered radioactivity in serum, 10% in liver, 7% in bone marrow, and 19% in bone with large patient to patient variation. The mean tumor/normal tissue radioactivity ratio varied between 3 and 25. On the assumption that the above radioactivity levels were achieved immediately following administration, that the radioactivity remained in situ until decayed and that the dimensions of tumor were sufficient to completely attenuate the emissions of 90Y, the dose to tumor for a 1-mCi administration would be approximately 50 rad with normal tissues receiving approximately 8 rad. PMID:3404257

  6. Phase I dose-escalation study of cabazitaxel administered in combination with gemcitabine in patients with metastatic or unresectable advanced solid malignancies.

    PubMed

    Rixe, Olivier; Puzanov, Igor; LoRusso, Patricia M; Cohen, Roger B; Morris, John C; Olowokure, Olugbenga O; Yin, Jian Y; Doroumian, Séverine; Shen, Liji; Olszanski, Anthony J

    2015-08-01

    Taxane-gemcitabine combinations have demonstrated antitumor activity. This phase I study (NCT01001221) aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus gemcitabine and to assess the preliminary efficacy of this combination. The patients included had metastatic or unresectable solid tumors and had exhausted standard treatment. Cohorts of three to six patients received cabazitaxel (15-20 mg/m) before (part 1a) or after (part 1b) gemcitabine (700-1000 mg/m) on Day 1 and gemcitabine alone on Day 8. Prophylactic growth factors were not allowed in cycle 1. In part 1a (n=12), five patients received 20 mg/m cabazitaxel plus 1000 mg/m gemcitabine (20/1000), five received 15/900, two received 15/700. In part 1b, all six patients received the lowest dose (700/15). At all doses, two or more patients experienced a DLT, regardless of administration sequence, including febrile neutropenia (n=4), grade 4 neutropenia (n=2), grade 4 thrombocytopenia (n=2), and grade 3 aspartate transaminase increase (n=1). The MTD was not established as all cohorts exceeded the MTD by definition. All patients experienced an adverse event; the most frequent all-grade nonhematologic events were fatigue (66.7%), decreased appetite (50.0%), and diarrhea (44.4%). The most frequent grade 3-4 hematologic abnormalities were neutropenia (83.3%), leukopenia (77.8%), and lymphopenia (72.2%). Toxicity was sequence-independent but appeared worse with gemcitabine followed by cabazitaxel. Durable partial responses were observed in three patients (prostate cancer, appendiceal cancer, and melanoma). The unacceptable DLTs with cabazitaxel plus gemcitabine, at doses reduced more than 25% from single-agent doses, preclude further investigation. PMID:26020806

  7. Urinary Adiponectin Excretion

    PubMed Central

    von Eynatten, Maximilian; Liu, Dan; Hock, Cornelia; Oikonomou, Dimitrios; Baumann, Marcus; Allolio, Bruno; Korosoglou, Grigorios; Morcos, Michael; Campean, Valentina; Amann, Kerstin; Lutz, Jens; Heemann, Uwe; Nawroth, Peter P.; Bierhaus, Angelika; Humpert, Per M.

    2009-01-01

    OBJECTIVE Markers reliably identifying vascular damage and risk in diabetic patients are rare, and reports on associations of serum adiponectin with macrovascular disease have been inconsistent. In contrast to existing data on serum adiponectin, this study assesses whether urinary adiponectin excretion might represent a more consistent vascular damage marker in type 2 diabetes. RESEARCH DESIGN AND METHODS Adiponectin distribution in human kidney biopsies was assessed by immunohistochemistry, and urinary adiponectin isoforms were characterized by Western blot analysis. Total urinary adiponectin excretion rate was measured in 156 patients with type 2 diabetes who had a history of diabetic nephropathy and 40 healthy control subjects using enzyme-linked immunosorbent assay. Atherosclerotic burden was assessed by common carotid artery intima-media-thickness (IMT). RESULTS A homogenous staining of adiponectin was found on the endothelial surface of glomerular capillaries and intrarenal arterioles in nondiabetic kidneys, whereas staining was decreased in diabetic nephropathy. Low-molecular adiponectin isoforms (∼30–70 kDa) were detected in urine by Western blot analysis. Urinary adiponectin was significantly increased in type 2 diabetes (7.68 ± 14.26 vs. control subjects: 2.91 ± 3.85 μg/g creatinine, P = 0.008). Among type 2 diabetic patients, adiponectinuria was associated with IMT (r = 0.479, P < 0.001) and proved to be a powerful independent predictor of IMT (β = 0.360, P < 0.001) in multivariable regression analyses. In a risk prediction model including variables of the UK Prospective Diabetes Study coronary heart disease risk engine urinary adiponectin, but not the albumin excretion rate, added significant value for the prediction of increased IMT (P = 0.007). CONCLUSIONS Quantification of urinary adiponectin excretion appears to be an independent indicator of vascular damage potentially identifying an increased risk for vascular events. PMID:19509019

  8. The Dose-response of Intrathecal Ropivacaine Co-administered with Sufentanil for Cesarean Delivery under Combined Spinal-epidural Anesthesia in Patients with Scarred Uterus

    PubMed Central

    Xiao, Fei; Xu, Wen-Ping; Zhang, Yin-Fa; Liu, Lin; Liu, Xia; Wang, Li-Zhong

    2015-01-01

    Background: Spinal anesthesia is considered as a reasonable anesthetic option in lower abdominal and lower limb surgery. This study was to determine the dose-response of intrathecal ropivacaine in patients with scarred uterus undergoing cesarean delivery under combined spinal-epidural anesthesia. Methods: Seventy-five patients with scarred uterus undergoing elective cesarean delivery under combined spinal-epidural anesthesia were enrolled in this randomized, double-blinded, dose-ranging study. Patients received 6, 8, 10, 12, or 14 mg intrathecal hyperbaric ropivacaine with 5 μg sufentanil. Successful spinal anesthesia was defined as a T4 sensory level achieved with no need for epidural supplementation. The 50% effective dose (ED50) and 95% effective dose (ED95) were calculated with a logistic regression model. Results: ED50 and ED95 of intrathecal hyperbaric ropivacaine for patients with scarred uterus undergoing cesarean delivery under combined spinal-epidural anesthesia (CSEA) were 8.28 mg (95% confidence interval [CI]: 2.28–9.83 mg) and 12.24 mg (95% CI: 10.53–21.88 mg), respectively. Conclusion: When a CSEA technique is to use in patients with scarred uterus for an elective cesarean delivery, the ED50 and ED95 of intrathecal hyperbaric ropivacaine along with 5 μg sufentanil were 8.28 mg and 12.24 mg, respectively. In addition, this local anesthetic is unsuitable for emergent cesarean delivery, but it has advantages for ambulatory patients. PMID:26415793

  9. Japanese consensus guidelines for pediatric nuclear medicine. Part 1: Pediatric radiopharmaceutical administered doses (JSNM pediatric dosage card). Part 2: Technical considerations for pediatric nuclear medicine imaging procedures.

    PubMed

    Koizumi, Kiyoshi; Masaki, Hidekazu; Matsuda, Hiroshi; Uchiyama, Mayuki; Okuno, Mitsuo; Oguma, Eiji; Onuma, Hiroshi; Kanegawa, Kimio; Kanaya, Shinichi; Kamiyama, Hiroshi; Karasawa, Kensuke; Kitamura, Masayuki; Kida, Tetsuo; Kono, Tatsuo; Kondo, Chisato; Sasaki, Masayuki; Terada, Hitoshi; Nakanishi, Atsushi; Hashimoto, Teisuke; Hataya, Hiroshi; Hamano, Shin-ichiro; Hirono, Keishi; Fujita, Yukihiko; Hoshino, Ken; Yano, Masayuki; Watanabe, Seiichi

    2014-06-01

    The Japanese Society of Nuclear Medicine has recently published the consensus guidelines for pediatric nuclear medicine. This article is the English version of the guidelines. Part 1 proposes the dose optimization in pediatric nuclear medicine studies. Part 2 comprehensively discusses imaging techniques for the appropriate conduct of pediatric nuclear medicine procedures, considering the characteristics of imaging in children. PMID:24647992

  10. High-flux hemodialysis after administering high-dose methotrexate in a patient with posttransplant lymphoproliferative disease and impaired renal function

    PubMed Central

    Reshetnik, Alexander; Scheurig-Muenkler, Christian; van der Giet, Markus; Tölle, Markus

    2015-01-01

    Key Clinical Message A young patient develops cerebral posttransplant lymphoproliferative disorder. Despite concurrent significantly impaired transplant kidney function use of add-on high-flux hemodialysis for additional clearance made the administration of high-dose methotrexate feasible in this patient without occurence of acute chronic kidney failure and significant hematological toxicity. PMID:26576275

  11. Biliary excretion of radioactivity after intravenous administration of (3H)25-hydroxyvitamin D3 in man

    SciTech Connect

    Ledger, J.E.; Watson, G.J.; Compston, J.E.

    1986-04-01

    The biliary excretion of radioactivity after intravenous (3H)25-hydroxyvitamin D3 was studied in nine patients with T-tube bile drainage. The mean +/- SD 24-hr radioactivity excretion in T-tube bile expressed as a percentage of the administered dose was 6.7 +/- 2.9%; after correction for incomplete bile collection, the value obtained was 16.0 +/- 11.1%. Chloroform solubility of biliary radioactivity increased from 27.4 +/- 8.9% to 72.9 +/- 10.1% following incubation with beta-glucuronidase. High-performance liquid chromatographic analysis of chloroform extracts of bile revealed that most of the eluted radioactivity was more polar than (3H)25-hydroxyvitamin D3. No free (3H)25-hydroxyvitamin D3 was demonstrated. Thus in man, most of the biliary radioactivity excreted following (3H)25-hydroxyvitamin D3 is in the form of water-soluble compounds, mainly glucuronides. However, our results suggest that glucuronides of metabolites other than 25-OHD3 are predominantly formed.

  12. Dosimetry analyses comparing high-dose-rate brachytherapy, administered as monotherapy for localized prostate cancer, with stereotactic body radiation therapy simulated using CyberKnife.

    PubMed

    Fukuda, Shoichi; Seo, Yuji; Shiomi, Hiroya; Yamada, Yuji; Ogata, Toshiyuki; Morimoto, Masahiro; Konishi, Koji; Yoshioka, Yasuo; Ogawa, Kazuhiko

    2014-11-01

    The purpose of this study was to perform dosimetry analyses comparing high-dose-rate brachytherapy (HDR-BT) with simulated stereotactic body radiotherapy (SBRT). We selected six consecutive patients treated with HDR-BT monotherapy in 2010, and a CyberKnife SBRT plan was simulated for each patient using computed tomography images and the contouring set used in the HDR-BT plan for the actual treatment, but adding appropriate planning target volume (PTV) margins for SBRT. Then, dosimetric profiles for PTVs of the rectum, bladder and urethra were compared between the two modalities. The SBRT plan was more homogenous and provided lower dose concentration but better coverage for the PTV. The maximum doses in the rectum were higher in the HDR-BT plans. However, the HDR-BT plan provided a sharper dose fall-off around the PTV, resulting in a significant and considerable difference in volume sparing of the rectum with the appropriate PTV margins added for SBRT. While the rectum D5cm(3) for HDR-BT and SBRT was 30.7 and 38.3 Gy (P < 0.01) and V40 was 16.3 and 20.8 cm(3) (P < 0.01), respectively, SBRT was significantly superior in almost all dosimetric profiles for the bladder and urethra. These results suggest that SBRT as an alternative to HDR-BT in hypofractionated radiotherapy for prostate cancer might have an advantage for bladder and urethra dose sparing, but for the rectum only when proper PTV margins for SBRT are adopted. PMID:24957754

  13. Synthesis and dose interval dependent hepatotoxicity evaluation of intravenously administered polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticle on Wistar rats.

    PubMed

    Rajan, Balan; Sathish, Shanmugam; Balakumar, Subramanian; Devaki, Thiruvengadam

    2015-03-01

    Superparamagnetic iron oxide nanoparticles are being used in medical imaging, drug delivery, cancer therapy, and so on. However, there is a direct need to identify any nanotoxicity associated with these nanoparticles. However uncommon, drug-induced liver injury (DILI) is a major health concern that challenges pharmaceutical industry and drug regulatory agencies alike. In this study we have synthesized and evaluated the dose interval dependent hepatotoxicity of polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticles (PUSPIOs). To assess the hepatotoxicity of intravenously injected PUSPIOs, alterations in basic clinical parameters, hematological parameters, hemolysis assay, serum levels of liver marker enzymes, serum and liver lipid peroxidation (LPO) levels, enzymatic antioxidant levels, and finally histology of liver, kidney, spleen, lung, brain, and heart tissues were studied in control and experimental Wistar rat groups over a 30-day period. The results of our study showed a significant increase in the aspartate transaminase (AST) enzyme activity at a dose of 10mg/kg b.w. PUSPIOs twice a week. Besides, alanine transaminase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (γGT) enzyme activity showed a slender increase when compared with control experimental groups. A significant increase in the serum and liver LPO levels at a dose of 10mg/kg b.w. PUSPIOs twice a week was also observed. Histological analyses of liver, kidney, spleen, lung, brain and heart tissue samples showed no obvious uncharacteristic changes. In conclusion, PUSPIOs were found to posses excellent biocompatibility and Wistar rats showed much better drug tolerance to the dose of 10mg/kg b.w. per week than the dose of 10mg/kg b.w. twice a week for the period of 30 days. PMID:25721486

  14. Urinary Excretion of N-Nitroso Compounds in Rats Fed Sodium Nitrite and/or Hot Dogs

    PubMed Central

    2015-01-01

    Nitrite-treated meat is a reported risk factor for colon cancer. Mice that ingested sodium nitrite (NaNO2) or hot dogs (a nitrite-treated product) showed increased fecal excretion of apparent N-nitroso compounds (ANC). Here, we investigated for the first time whether rats excrete increased amounts of ANC in their urine after they are fed NaNO2 and/or hot dogs. Rats were treated for 7 days with NaNO2 in drinking water or were fed hot dogs. Their 24 h urine samples were analyzed for ANC by thermal energy analysis on days 1–4 after nitrite or hot dog treatment was stopped. For two rats fed 480 mg NaNO2/L drinking water, mean urinary ANC excretion on days 1–4 was 30, 5.2, 2.5, and 0.8 nmol/day, respectively. For two to eight rats/dose given varied NaNO2 doses, mean urinary ANC output on day 1 increased from 0.9 (for no nitrite) to 37 (for 1000 mg NaNO2/L drinking water) nmol ANC/day. Urine samples of four rats fed 40–60% hot dogs contained 12–13 nmol ANC on day 1. Linear regression analysis showed highly significant correlations between urinary ANC excretion on day 1 after stopping treatment and varied (a) NaNO2 level in drinking water for rats fed semipurified or commercials diet and (b) hot dog levels in the diet. Some correlations remained significant up to 4 days after nitrite treatment was stopped. Urinary output of ANC precursors (compounds that yield ANC after mild nitrosation) for rats fed semipurified or commercial diet was 11–17 or 23–48 μmol/day, respectively. Nitrosothiols and iron nitrosyls were not detected in urinary ANC and ANCP. Excretion of urinary ANC was about 60% of fecal ANC excretion for 1 to 2 days after NaNO2 was fed. Administered NaNO2 was not excreted unchanged in rat urine. We conclude that urinary ANC excretion in humans could usefully be surveyed to indicate exposure to N-nitroso compounds. PMID:25183213

  15. Population pharmacokinetics of mefloquine, administered as a fixed-dose combination of artesunate-mefloquine in Indian patients for the treatment of acute uncomplicated Plasmodium falciparum malaria

    PubMed Central

    2014-01-01

    Background Fixed-dose combinations of artemisinin combination therapy are strongly recommended to facilitate drug administration and compliance. New fixed-dose combinations must nevertheless be evaluated in relevant populations in terms of efficacy and pharmacokinetics. Methods A single-arm, open-label, clinical trial was performed in Indian patients with acute uncomplicated Plasmodium falciparum malaria to investigate the efficacy and the pharmacokinetics of mefloquine when combined with artesunate in a fixed-dose combination (400/200 mg of mefloquine base/artesunate). The pharmacokinetic analysis was performed using a population approach. Results Seventy-seven patients were included in the study. Mefloquine pharmacokinetics obeys a two-compartment model with first-order absorption and elimination. Mean parameter estimates (% inter-individual variability) were as follows: 0.16 h-1 (75%) for the absorption rate constant, 1.13 L/h (30%) for the apparent plasma clearance, 271 L (21%) for the apparent central distribution volume, 344 L (54%) for the apparent peripheral distribution volume, and 1.43 L/h for the apparent distribution clearance. These values were consistent with the pharmacokinetic results described in Thai patients. No significant covariate was found for clearance. Body weight explained the inter-individual variability of the apparent central and peripheral distribution volumes. The PCR-adjusted efficacy of the treatment was 100%. Conclusions The lack of significant covariate explaining the inter-individual variability of mefloquine clearance, combined with the excellent efficacy, supports the use of the standard 200/400 mg of artesunate-mefloquine fixed-dose combination in Indian patients with uncomplicated P. falciparum malaria. Trial Registration Clinical Trial Registration: ISRCTN70618692 PMID:24886117

  16. Serum Insulin Aspart Concentrations Following High-Dose Insulin Aspart Administered Directly into the Duodenum of Healthy Subjects: An Open-Labeled, Single-Blinded, and Uncontrolled Exploratory Trial

    PubMed Central

    Ihlo, Charlotte A.; Aksglæde, Karin Bak; Laursen, Torben; Lauritzen, Torsten; Christiansen, Jens Sandahl

    2009-01-01

    Objective The goal of this study was to determine the bioavailability of high-dose insulin aspart administered directly into the duodenum of healthy subjects. Methods In a pilot study, four subjects each received four escalating doses of a 1-ml solution of insulin aspart (100, 300, 600, and 1000 IU, respectively) directly into the duodenum. In the following main study, eight subjects each received two identical doses of insulin aspart of 1000 IU, in 4- and 8-ml solutions, respectively, directly into the duodenum. Subjects in the main study also received an intravenous and a subcutaneous injection of 4 to 6 IU of insulin aspart. Results A considerable number of samples and, in some cases, consecutive samples revealed significantly increased concentrations of serum insulin aspart. Despite the significant serum insulin aspart concentrations, no significant changes of plasma glucose were measured. Moreover, no significant suppression of endogenous insulin secretion was detected, as assessed by the levels of serum human insulin. Conclusions Administration of high-dose insulin aspart directly into the duodenum of healthy subjects resulted in significantly increased serum insulin aspart concentrations in a high number of consecutive samples using a specific enzyme-linked immunosorbent assay. However, no significant changes in the levels of plasma glucose or serum human insulin were observed. Thus, the study did not provide any evidence of biological activity of the original insulin aspart molecule after high-dose administration directly into the duodenum. PMID:20144435

  17. Two doses of parenterally administered split influenza virus vaccine elicited high serum IgG concentrations which effectively limited viral shedding upon challenge in mice.

    PubMed

    Hovden, A-O; Cox, R J; Madhun, A; Haaheim, L R

    2005-10-01

    We have previously found that whole influenza virus vaccine induced a more rapid and stronger humoral response, particularly after the first dose of vaccine, than split virus vaccine in mice. In this study, we have evaluated the protective efficacy of whole and split influenza virus vaccines in mice using a nonlethal upper respiratory tract challenge model. We have also investigated the immunological correlates associated with no or very little viral shedding after viral challenge. Vaccination resulted in reduced viral shedding and shortened the duration of infection by at least 2 days. After one dose of vaccine, whole virus vaccine generally resulted in less viral shedding than split virus vaccine. In contrast, two doses of split virus vaccine, particularly the highest vaccine strengths of 15 and 30 microg HA, most effectively limited viral replication and these mice had high concentrations of prechallenge influenza-specific serum IgG. The vaccine formulation influenced the IgG2a/IgG1 ratio, and this IgG subclass profile was maintained upon challenge to some extent, although it did not influence the level of viral shedding. The concentration of postvaccination serum IgG showed an inverse relationship with the level of viral shedding after viral challenge. Therefore, serum IgG is an important factor in limiting viral replication in the upper respiratory tract upon challenge of an antigenically similar virus. PMID:16253121

  18. Use of a statistical model to predict the potential for repeated dose and developmental toxicity of dermally administered crude oil and relation to reproductive toxicity.

    PubMed

    McKee, Richard H; Nicolich, Mark; Roy, Timothy; White, Russell; Daughtrey, Wayne C

    2014-01-01

    Petroleum (commonly called crude oil) is a complex substance primarily composed of hydrocarbon constituents. Based on the results of previous toxicological studies as well as occupational experience, the principal acute toxicological hazards are those associated with exposure by inhalation to volatile hydrocarbon constituents and hydrogen sulfide, and chronic hazards are associated with inhalation exposure to benzene and dermal exposure to polycyclic aromatic compounds. The current assessment was an attempt to characterize the potential for repeated dose and/or developmental effects of crude oils following dermal exposures and to generalize the conclusions across a broad range of crude oils from different sources. Statistical models were used to predict the potential for repeated dose and developmental toxicity from compositional information. The model predictions indicated that the empirical data from previously tested crude oils approximated a "worst case" situation, and that the data from previously tested crude oils could be used as a reasonable basis for characterizing the repeated dose and developmental toxicological hazards of crude oils in general. PMID:24179028

  19. Cobalt excretion test for the assessment of body iron stores.

    PubMed

    Sorbie, J; Olatunbosun, D; Corbett, W E; Valberg, L S

    1971-05-01

    Iron absorption is under delicate control and the level of absorption is adjusted to comply with the body's need for iron. To measure the intestinal setting for iron absorption, and thereby indirectly assess body iron requirements, cobaltous chloride labelled with (57)Co or (60)Co was given by mouth and the percentage of the test dose excreted in the urine in 24 hours was measured in a gamma counter. Seventeen control subjects with normal iron stores excreted 18% (9-23%) of the dose. Increased excretion, 31% (23-42%), was found in 10 patients with iron deficiency anemia and in 15 patients with depleted iron stores in the absence of anemia. In contrast, 12 patients with anemia due to causes other than iron deficiency excreted amounts of radiocobalt within the normal control range. In patients with iron deficiency, replenishment of iron stores by either oral or parenteral iron caused the previously high results to return to normal.Excretion of the test dose was normal in portal cirrhosis with normal iron stores but it was markedly increased in patients with cirrhosis complicated by either iron deficiency or endogenous iron overload. It was also raised in primary hemochromatosis. Excretion of the dose was reduced in gluten-sensitive enteropathy. Gastrointestinal surgery and inflammatory disease of the lower small intestine had no effect on the results except that some patients with steatorrhea had diminished excretion.The cobalt excretion test provides the clinician with a tool for the assessment of iron absorption, the detection of a reduction in body iron stores below the level that is normal for the subject in question, the differentiation of iron deficiency anemia from anemia due to other causes, and the investigation of patients with iron-loading disorders. PMID:5578125

  20. Effects of sodium N-methyl-N-dithiocarboxyglucamine on cadmium distribution and excretion

    SciTech Connect

    Gale, G.R.; Shinobu, L.A.; Jones, M.M.; Atkins, L.M.; Smith, A.B.

    1984-12-17

    Sodium N-methyl-N-dithiocarboxyglucamine (MDCG) was evaluated for its efficacy in mobilizing and promoting excretion of metallothionein-bound /sup 109/Cd using mice which had received 0.03 mg of CdCl/sub 2/.2.5H/sub 2/O along with 1.0 ..mu..Ci of /sup 109/CdCl/sub 2/ three weeks earlier. The MDCG-induced change in the fecal excretion of Cd ranged from a 15-fold increase over the control rate at the lowest dose level used (2.2 mmol/kg; 684 mg/kg) up to a 72-fold increase at the highest dose (8.8 mmol/kg; 2736 mg/kg) following three daily injections. The latter treatment administered Cd over a 3-day period of observation. Urinary Cd excretion was insignificant in both the control and treated groups. The whole body burden of Cd was reduced by over 50% following seven thrice-weekly i.p. injections of MDCG at 8.8 mmol/kg. There was a 60-65% reduction in both the liver and kidney Cd levels following the same treatment regimen. Radioassay of ten other organs and tissues revealed only modest changes. Testicular Cd was decreased slightly at the highest dose level, and heart tissue from each treated group contained slightly more Cd than controls. Results indicated a rather marked specificity of MDCG in lowering the Cd content of two organs most susceptible to Cd-induced toxicity.

  1. Pharmacokinetics, bioavailability, tissue distribution, excretion, and metabolite identification of methoxyflavones in Kaempferia parviflora extract in rats.

    PubMed

    Mekjaruskul, Catheleeya; Jay, Michael; Sripanidkulchai, Bungorn

    2012-12-01

    Kaempferia parviflora (KP) is an herbal plant in the family of Zingiberaceae. KP mainly contains methoxyflavones, especially 5,7-dimethoxyflavone (DMF), 5,7,4'-trimethoxyflavone (TMF), and 3,5,7,3',4'-pentamethoxyflavone (PMF). The present study was designed to characterize the pharmacokinetics, including bioavailability, distribution, excretion, and identification of metabolites after administration of a KP ethanolic extract. Male rats were orally or intravenously administered a 250 mg/kg concentration of a KP extract, and blood samples were obtained at selected times to determine pharmacokinetic parameters of PMF, TMF, and DMF. For distribution and excretion studies, the organs, urine, and feces samples were collected at various times after oral administration of a larger (750 mg/kg) dose of KP extract. Methoxyflavones in the biological samples were quantified by high-performance liquid chromatography-UV, and the metabolites in urine and feces were further identified by using liquid chromatography-tandem mass spectrometry. After oral administration, concentrations of the three methoxyflavones quickly approached their maximal concentration, ranging from 0.55 to 0.88 μg/ml within 1 to 2 h after administration, and then were gradually excreted with half-lives of 3 to 6 h. The methoxyflavones showed low oral bioavailability of 1 to 4%. Three methoxyflavones were detected at their highest levels in liver followed by kidney. They were also found in lung, testes, and brain. After absorption, organ distribution, and metabolism, the components of KP were mainly eliminated through urine in the forms of demethylated, sulfated, and glucuronidated products and as demethylated metabolites in the feces. The parent compounds were found to have 0.79, 1.76, and 3.10% dose recovery in urine and 1.06, 1.77, and 0.96% dose recovery in feces for PMF, TMF, and DMF, respectively. These studies are the first to describe the pharmacokinetics of KP extract to provide the information on

  2. Effects of two human chorionic gonadotropin doses administered to the ovarian states during the in vitro fertilization and embryo transfer program

    PubMed Central

    MA, MINGXING; WANG, JIALIN; XU, LIJUN; ZHANG, QINXI; DU, BOTAO; JIANG, XIAOYING; SHI, QINGLI; ZHOU, LILI; LI, BAOXIN; SAITO, HIDEKAZU; KURACHI, HIROHISA

    2015-01-01

    The aim of the present study was to examine the effects of the human chorionic gonadotropin (hCG) dose on the pulsatility indices (PI) of the intraovarian artery on the day of follicle aspiration and the oocyte quality, intrafollicular oxidative stress and luteinization. PI was also measured on the day of hCG administration. A total of 15 patients were undergoing the in vitro fertilization and embryo transfer (IVF-ET) program. To estimate whether there was any difference between the intraovarian artery blood flow and oocyte development of the same patients treated with 5,000 or 10,000 IU hCG, the intraovarian artery blood flow was measured by transvaginal color ultrasonography pulsed wave Doppler, and the follicular fluids and the granulosa cells were collected at follicle aspiration. There were statistically significant differences between the same patients undergoing the two different hCG-dose treatments in which the first protocol included 10,000 IU and the second protocol included 5,000 IU hCG treatment. These differences were apparent in the PI of intraovarian artery blood flow on the day of follicle aspiration (P=0.0023), in the incidence of apoptosis in cumulus (ApoC) and mural (ApoM) granulosa cells (ApoC, P=0.0077; ApoM, P=0.0128), in the total oocytes retrieved (P=0.0342) and in the follicle fluid progesterone concentration (P=0.0044). There were no significant differences between the two protocols in the PI of intraovarian artery blood flow on the day of hCG administration (P=0.4326), serum steroid on the day of follicle aspiration [serum P, P>0.9999; serum estradiol (E2), P=0.8589], follicle fluid E2 concentration (P=0.8939), mature oocyte rate (P=0.3743) and total mature oocytes retrieved (P=0.2026). In conclusion, the dose of hCG administration can significantly affect the intraovarian artery blood flow and the development of follicles and oocytes in an IVF-ET program. PMID:26075075

  3. Efficacy and safety of ipratropium bromide/salbutamol sulphate administered in a hydrofluoroalkane metered-dose inhaler for the treatment of COPD

    PubMed Central

    Bhattacharya, Amal; Bhargava, Salil; Singh, Virendra; Talwar, Deepak; Whig, Jagdeep; Rebello, Juliet; Purandare, Shrinivas; Gogtay, Jaideep

    2016-01-01

    Background The use of chlorofluorocarbons (CFCs) has contributed to the depletion of the stratospheric ozone layer resulting in serious health concerns. Ipratropium bromide/salbutamol sulphate CFC-pressurized metered-dose inhalers (IB/SAL-CFC pMDI) have been in widespread use for many years without any apparent ill consequences. This combination has now been reformulated using the hydrofluoroalkane (HFA) propellant. This study sought to establish the clinical noninferiority of a new HFA-containing IB/SAL pMDI to the conventional IB/SAL-CFC pMDI in subjects with mild/moderate COPD. Methods This was a randomized, double-blind, parallel-group, multicenter study in two consecutive periods: a 14-day run-in period followed by a 85-day treatment period. Eligible mild-to-moderate stable COPD subjects aged 40−75 years were enrolled into the study and entered the run-in period during which subjects withdrew all the bronchodilators, except for salbutamol as rescue medication. Subjects were randomized to 85 days treatment with either IB/SAL-HFA or IB/SAL-CFC, 20 μg qid. Results Of the 290 randomized patients, 249 completed the study. The primary efficacy variable was the change in forced expiratory volume in one second from predose to 60 minutes after dosing on day 85. At the end of the treatment period, the adjusted mean change in forced expiratory volume in one second at 60 minutes was 123 mL in the IB/SAL-HFA pMDI group and 115 mL in the IB/SAL-CFC pMDI group. Because the lower limit of the 95% confidence interval for the between-group difference (−62 mL) was well within the noninferiority margin (−100 mL), the HFA formulation was deemed clinically noninferior to the CFC formulation. This finding was supported by secondary efficacy assessments. Both formulations of IB/SAL were well tolerated during the prolonged multiple dosing. Conclusion It is concluded that IB/SAL-HFA pMDI provides effective bronchodilation of similar degree to that achieved with IB/SAL-CFC p

  4. Pharmacokinetics, tissue distribution and excretion of peimisine in rats assessed by liquid chromatography-tandem mass spectrometry.

    PubMed

    Chen, Lihua; Li, Dongxun; Zhang, Guosong; Zhang, Wei; Zhang, Lihua; Guan, Yongmei; Zhu, Weifeng; Liu, Hongning

    2015-06-01

    Peimisine, the common ingredient of "zhebeimu" groups and "chuanbeimu" groups, is responsible for the expectorant and cough relieving effects. The aim of this study was to investigate the pharmacokinetics, tissue distribution and excretion of peimisine in male and female SD (Sprague-Dawley) rats by a rapid and sensitive LC-MS/MS (liquid chromatography-tandem mass spectrometry) method used carbamazepine as the internal standard after oral administration, carbamazepine was stated as an IS. The results showed that peimisine was slowly distributed, and eliminated from rat plasma and manifested linear dynamics in a dose range of 0.26-6.5 mg/kg. Tested by ANOVA, there were gender differences in the pharmacokinetic parameters of AUC(0-t), AUC(0-∞) among a single dose of 0.26, 1.3, 6.5 mg/kg (P < 0.05). Drug blood and tissue levels in male rats were significantly higher than the female counterparts after oral administration, while both the males and the females showed high drug levels in spleen, kidney, lung, liver and heart. On the other hand, the peimisine levels that can be reached in uterus, ovary, testis and brain is low. The excretion study showed that little administered peimisine (<0.7%) was recovered in the male and female bile. Approximately 13.46 and 15.05% were recovered in female urine and feces, while 43.07 and 7.49% were recovered in male urine and feces, respectively, which indicated that the major elimination route of male rats was urine excretion. In addition, there was significant differences in total cumulative excretive ratio of peimisine in feces (P < 0.05) and no significant differences in the urine (P > 0.05) at a dose of 1.3 mg/kg. PMID:25001900

  5. Homeostatic control of manganese excretion in the neonatal rat

    SciTech Connect

    Ballatori, N.; Miles, E.; Clarkson, T.W.

    1987-05-01

    Previous studies in neonatal and suckling animals showed that immature animals have a greatly diminished capacity to excrete manganese and therefore were considered to be unable to regulate tissue manganese concentrations. In contrast, the present studies indicate that suckling rats have the capacity to excrete excess manganese at rates nearly comparable to those of adults. Eight- to 10-day-old rats given a tracer dose of /sup 54/MnCl/sub 2/ (essentially carrier free), either via gavage or by intraperitoneal injection showed little elimination of the /sup 54/Mn until the 18-19th day of life, when there was an abrupt increase in the rate of the metal's excretion. However, when manganese was given in doses of 1 and 10 mg/kg, the young animals excreted from 30-70% of the dose in only 4 days, at which time a new rate of excretion was achieved. This enhanced rate of excretion remained constant until the 18-19th day of life, when it was again accelerated. Biliary excretion of manganese, the primary route for the elimination of the metal, was only 30-60% lower in 14-day-old rats compared with adults at doses ranging from tracer to 10 mg /sup 54/Mn/kg. For both the 14-day-old and adult rats, an apparent biliary transport maximum was reached at a dose of 10 mg Mn/kg. These studies indicate that the excretory pathways for manganese are well developed in the neonatal rat. The avid retention of tracer quantities of manganese by the neonate may be a consequence of the scarcity of this essential trace metal in its diet.

  6. Effect of aspartame and protein, administered in phenylalanine-equivalent doses, on plasma neutral amino acids, aspartate, insulin and glucose in man.

    PubMed

    Møller, S E

    1991-05-01

    Six human males each received 0.56 g phenylalanine (Phe) in the form of 1.0 g aspartame or 12.2 g bovine albumin in 200 ml water or water alone. Venous blood samples collected before consumption and during the following 4 hr were assayed for plasma levels of large, neutral amino acids (LNAA), aspartate, insulin and glucose. The area under the curve for plasma Phe was 40% greater, although not significant, after aspartame compared with albumin intake. The indicated increased clearance rate of plasma Phe after albumin may be caused by the significant increase of insulin, on which aspartame had no effect. There was a significant main effect of aspartame for plasma tyrosine but not for tryptophan, valine, isoleucine or leucine. Plasma aspartate was significantly increased at 0.25 hr after the aspartame intake. The percentage Phe/LNAA decreased slightly in response to albumin but increased 55% after aspartame and remained significantly increased for 2 hr. Tyrosine/LNAA increased and tryptophan/LNAA decreased modestly after aspartame intake. The study showed that the intake of aspartame in a not unrealistically high dose produced a marked and persistent increase of the availability of Phe to the brain, which was not observed after protein intake. The study indicated, furthermore, that Phe was cleared faster from the plasma after consumption of protein compared with aspartame. PMID:1946186

  7. Bioavailability of intramuscularly administered tenoxicam.

    PubMed

    Stebler, T; Guentert, T W

    1993-08-01

    Bioavailability of intramuscularly administered tenoxicam relative to single oral and relative to intravenous doses was determined in two separate randomized crossover studies. Twelve healthy volunteers (12 males, age 20-30 years) received a rapid intravenous injection and a single intramuscular dose and 12 other subjects (11 males, 1 female, age 21-25 years) a single oral and a single intramuscular dose of 20 mg of tenoxicam on two different occasions. The wash-out period between the two consecutive treatments was 4 weeks. Plasma concentrations after dosing were determined by a specific HPLC method. Differences in tenoxicam concentration-time profiles after the different routes of administration were limited to the first 2 h after dosing. Later, plasma concentrations were almost superimposable within and across the two studies. The extent of absorption of intramuscularly administered tenoxicam was complete (mean +/- CV per cent: F(abs) 0.99 +/- 20 per cent) with no difference between the two extravascular administrations (F(rel) 0.95 +/- 10 per cent, intramuscular vs oral). After intramuscular administration tenoxicam was more rapidly absorbed compared to the oral dose (Tmax 0.71 h +/- 80 per cent vs 1.4 h +/- 62 per cent; p > 0.05). Peak concentrations after oral and intramuscular administration (Cmax 2.5 mg l-1 +/- 19 per cent vs 2.7 mg l-1 +/- 14 per cent; p < 0.05) were very similar. PMID:8218966

  8. Radioactive iodide (131 I-) excretion profiles in response to potassium iodide (KI) and ammonium perchlorate (NH4ClO4) prophylaxis.

    PubMed

    Harris, Curtis; Dallas, Cham; Rollor, Edward; White, Catherine; Blount, Benjamin; Valentin-Blasini, Liza; Fisher, Jeffrey

    2012-08-01

    Radioactive iodide ((131)I-) protection studies have focused primarily on the thyroid gland and disturbances in the hypothalamic-pituitary-thyroid axis. The objective of the current study was to establish (131)I- urinary excretion profiles for saline, and the thyroid protectants, potassium iodide (KI) and ammonium perchlorate over a 75 hour time-course. Rats were administered (131)I- and 3 hours later dosed with either saline, 30 mg/kg of NH(4)ClO(4) or 30 mg/kg of KI. Urinalysis of the first 36 hours of the time-course revealed that NH(4)ClO(4) treated animals excreted significantly more (131)I- compared with KI and saline treatments. A second study followed the same protocol, but thyroxine (T(4)) was administered daily over a 3 day period. During the first 6-12 hour after (131)I- dosing, rats administered NH(4)ClO(4) excreted significantly more (131)I- than the other treatment groups. T(4) treatment resulted in increased retention of radioiodide in the thyroid gland 75 hour after (131)I- administration. We speculate that the T(4) treatment related reduction in serum TSH caused a decrease synthesis and secretion of thyroid hormones resulting in greater residual radioiodide in the thyroid gland. Our findings suggest that ammonium perchlorate treatment accelerates the elimination rate of radioiodide within the first 24 to 36 hours and thus may be more effective at reducing harmful exposure to (131)I- compared to KI treatment for repeated dosing situations. Repeated dosing studies are needed to compare the effectiveness of these treatments to reduce the radioactive iodide burden of the thyroid gland. PMID:23066407

  9. Tissue accumulation and urinary excretion of Cr in chromium picolinate (CrPic)-supplemented lambs.

    PubMed

    Dallago, Bruno Stéfano Lima; Lima, Bárbara Alcântara Ferreira; Braz, Shélida Vasconcelos; Mustafa, Vanessa da Silva; McManus, Concepta; Paim, Tiago do Prado; Campeche, Aline; Gomes, Edgard Franco; Louvandini, Helder

    2016-05-01

    Chromium (Cr) concentrations in liver, kidney, spleen, heart, lymph node, skeletal muscle, bone, testis and urine of lambs were measured to trace the biodistribution and bioaccumulation of Cr after oral supplementation with chromium picolinate (CrPic). Twenty-four Santa Inês lambs were treated with four different concentrations of CrPic: placebo, 0.250, 0.375 and 0.500 mg of CrPic/animal/day for 84 days. The basal diet consisted of Panicum maximum cv Massai hay and concentrate. Cr concentrations were measured by ICP-MS measuring (52)Cr as collected mass. There was a positive linear relationship between dose administered and the accumulation of Cr in the heart, lungs and testis. Urinary excretion of Cr occurred in a time and dose-dependent manner, so the longer or more dietary Cr provided, the greater excretion of the element. As some non-carcass components (such as lungs or heart) are added to bone and visceral meal to feed animals, there is a risk of bioaccumulation and biomagnification due to Cr offered as CrPic in the diet. PMID:27049124

  10. Radioactive excretion in human milk following administration of /sup 99m/Tc macroaggregated albumin

    SciTech Connect

    Pittard, W.B.; Merkatz, R.; Fletcher, B.D.

    1982-08-01

    Albumin-tagged sodium pertechnetate (technetium) is routinely used in nuclear medicine for scanning procedures of the lung. The rate of excretion of this radionuclide into breast milk and the resultant potential radiation hazard to the nursing infant have received little attention. Therefore the milk from a nursing mother who required a lung scan because of suspected pulmonary emboli using an intravenous injection of 4 mCi of /sup 99m/Tc macroaggregated human serum albumin was monitored. Albumin tagging severely limited the entrance of technetium into her milk and the radioactivity of the milk returned to base line by 24 hours. A total of 2.02 muCi of technetium was measured in the 24-hour milk collection after technetium injection and 94% of this amount was excreted by 15.5 hours. This amount of technetium administered orally to a newborn would deliver a total body radiation dose of .3 mrad. Therefore, an infant would receive trivial doses of radiation if breast-feeding were resumed 15.5 hours after administration of the radionuclide to the mother and nursing can clearly be resumed safely 24 hours after injection.

  11. High doses of intravenously administered titanium dioxide nanoparticles accumulate in the kidneys of rainbow trout but with no observable impairment of renal function.

    PubMed

    Scown, Tessa M; van Aerle, Ronny; Johnston, Blair D; Cumberland, Susan; Lead, Jamie R; Owen, Richard; Tyler, Charles R

    2009-06-01

    Our recent work suggests limited uptake of unstabilized metal oxide nanoparticles via water into fish, however, some other studies have indicated such exposures can induce oxidative stress. To investigate tissue distribution and toxicity of titanium dioxide (TiO(2)) nanoparticles that may enter into fish, we conducted a series of injection studies. Rainbow trout (Oncorhynchus mykiss) were intravenously injected with 100 microg TiO(2) nanoparticles and the content of titanium in blood, brain, gills, liver, and kidney quantified at time points between 6 h and 90 days using inductively coupled plasma optical emission spectroscopy. Injected Ti was concentrated in the kidneys and remained there up to 21 days, however, there was evidence of clearance of TiO(2) at 90 days. Ti accumulation in the liver was 15 times lower than in the kidney with no apparent clearance. Using TEM we showed nanoparticles were localized in tissue vesicles surrounding the kidney tubules. In a second injection study, rainbow trout were injected with 100 microg TiO(2) and plasma samples from individual fish analyzed for total protein and creatinine content at time points between 6 h and 21 days to assess for possible effects on kidney function. No effect of TiO(2) on total plasma protein content or creatinine concentrations were found indicating that neither urine production nor glomerular filtration rate were affected. We conclude that in trout upon a single high dose exposure of TiO(2) nanoparticles via the bloodstream, TiO(2) accumulates in the kidneys but has minimal effect on kidney function. PMID:19332650

  12. Developmental toxicity of clarified slurry oil, syntower bottoms, and distillate aromatic extract administered as a single oral dose to pregnant rats

    SciTech Connect

    Feuston, M.H.; Mackerer, C.R.

    1996-09-01

    Clarified slurry oil (CSO), syntower bottoms (STB), and distillate aromatic extract (DAE) are refinery streams produced by processing crude oil. Available data indicate that some refinery streams are developmentally toxic by the dermal route of exposure. However, there is no conclusive evidence for their being teratogenic. The present studies were designed to further explore the suspected teratogenic potency of refinery streams while at the same time limiting embryolethality. In general, evidence of maternal toxicity (i.e., decreased body weight gain, decreased thymus weight) was observed at doses greater than or equal to 500 mg/kg. For each refinery stream tested, the incidence of resorption was greatest on GD 11. A common pattern of fetal malformations was observed for all of the refinery streams tested and included cleft palate, diaphragmatic hernia, and paw and tail defects. The incidence and type of malformation observed were influenced by the gestation day of exposure. The incidence and type of malformation observed were influenced by the gestation day of exposure. The incidences of external and skeletal malformations were greatest on GD 11 and 12 for fetuses exposed to CSO; on GD 13 and 14, the incidence of malformation was comparable for CSO- and STB-exposed fetuses. The incidence of visceral anomalies was greatest on GD 11-13 for fetuses exposed to CSO and STB; on Gestation D 14, the incidence was comparable for each of the refinery streams tested. In general, the ability to produce adverse effects on development was greatest for CSO and least for DAE. Effects produced by STB were comparable to or less severe than those observed for CSO. 24 refs., 11 tabs.

  13. [Study of serum concentrations and urinary excretion of secnidazole after oral administration in man. Comparison with tinidazole].

    PubMed

    Populaire, P; Decouvelaere, B; Renard, A; Pasquier, P

    1980-11-01

    Secnidazole, a derivative of 5-nitro imidazole exhibits trichomonacid, amoebicid and antimicrobial properties; it has been studied in view of its biological fate in healthy volunteers (man and woman) comparatively with tinidazole. Both products were administered orally to the same volunteers at the single dose level of 2 g. The seric concentrations and the pharmacokinetic profile were determined up to the 72nd hour after drug administration. The whole urinary excretion (unchanged product + metabolites) during the same period was determined in percent of the administered dose level. Secnidazole is particularly different from tinidazole owing to its slower blood clearance. The apparent average half-life in the ten volunteers (5 men and 5 women) is about 17 hours for secnidazole and 13 hours for tinidazole. However, for both drugs, a difference between men and women was demonstrated: in female volunteers, the decrease in blood concentrations occurs a little quicker than in male volunteers. Regarding urinary excretion, it is also a little greater in female volunteers than in male volunteers. PMID:7003510

  14. Treatment of primary Sjögren's syndrome with low-dose natural human interferon-alpha administered by the oral mucosal route: a phase II clinical trial. IFN Protocol Study Group.

    PubMed

    Ship, J A; Fox, P C; Michalek, J E; Cummins, M J; Richards, A B

    1999-08-01

    The purpose of this investigation was to examine the safety and efficacy of four dosages of natural human interferon-alpha (nHuIFN-alpha) delivered over a 12-week period orally in lozenges (150 IU and 450 IU, once [QD] or three times [TID] daily) compared to placebo in subjects with primary Sjögren's syndrome. This randomized, double-blinded clinical trial demonstrated that nHuIFN-alpha at a dose of 150 IU administered TID by oral lozenge significantly improved stimulated whole saliva output compared to placebo after 12 weeks of treatment. The 150 IU TID dose also was suggestive of benefit for 5 of 7 subjective measures of oral and ocular comfort. IFN lozenges demonstrated a good safety profile, with no serious adverse events found in any treatment group. There were no significant differences between the placebo and the four doses of IFN for adverse events by total number, organ system, severity, dropouts, and number judged to be related to treatment. In conclusion, these results demonstrated that the use of 150 IU IFN lozenges TID for 12 weeks in subjects with primary Sjögren's syndrome improved salivary output and decreased complaints of xerostomia without causing significant adverse medical events. PMID:10476942

  15. Metabolism and excretion of 2-ethoxyethanol in the adult male rat.

    PubMed Central

    Cheever, K L; Plotnick, H B; Richards, D E; Weigel, W W

    1984-01-01

    The routes of 14C excretion following the administration of a single oral 230 mg/kg body weight dose of 2-ethoxyethanol [ethanol-1,2-14C] or 2-ethoxyethanol [ethoxy-1-14C] to male Sprague-Dawley rats were investigated. Elimination of the 14C by the urinary route accounted for 76 to 80% of the dose within 96 hr. The main pathway of biotransformation is oxidation to the corresponding acid, with some subsequent conjugation of the acid metabolite with glycine. The major metabolites, ethoxyacetic acid and N-ethoxy-acetyl glycine, representing 73 to 76% of the administered dose, were eliminated in the urine. The major difference in the metabolic profiles of the two radiochemicals was in the rate and amount of 14CO2 expired via the lung. Of the administered 14C, 11.7% of the ethoxy-labeled and 4.6% of the ethanol-labeled compounds were eliminated as CO2. The biological half-time was 9.9 +/- 1.5 hr for the ethoxy-labeled compound and 12.5 +/- 1.9 hr for the ethanol label. After administration of the ethanol-labeled compound, the only radiolabeled component found in the rat testes was identified as ethoxyacetic acid. Results of this study suggest that the reported testicular effects in the rat may be a result of tissue levels of ethoxyacetic acid. PMID:6437805

  16. Sub-Chronic Oral Exposure to Iridium (III) Chloride Hydrate in Female Wistar Rats: Distribution and Excretion of the Metal

    PubMed Central

    Iavicoli, Ivo; Fontana, Luca; Bergamaschi, Antonio; Conti, Marcelo Enrique; Pino, Anna; Mattei, Daniela; Bocca, Beatrice; Alimonti, Alessandro

    2012-01-01

    Iridium tissue distribution and excretion in female Wistar rats following oral exposure to iridium (III) chloride hydrate in drinking water (from 1 to 1000 ng/ml) in a sub-chronic oral study were determined. Samples of urine, feces, blood and organs (kidneys, liver, lung, spleen and brain) were collected at the end of exposure. The most prominent fractions of iridium were retained in kidney and spleen; smaller amounts were found in lungs, liver and brain. Iridium brain levels were lower than those observed in other tissues but this finding can support the hypothesis of iridium capability to cross the blood brain barrier. The iridium kidney levels rose significantly with the administered dose. At the highest dose, important amounts of the metal were found in serum, urine and feces. Iridium was predominantly excreted via feces with a significant linear correlation with the ingested dose, which is likely due to low intestinal absorption of the metal. However, at the higher doses iridium was also eliminated through urine. These findings may be useful to help in the understanding of the adverse health effects, particularly on the immune system, of iridium dispersed in the environment as well as in identifying appropriate biological indices of iridium exposure. PMID:22942873

  17. Urinary MDMA, MDA, HMMA, and HMA Excretion Following Controlled MDMA Administration to Humans

    PubMed Central

    Abraham, Tsadik T.; Barnes, Allan J.; Lowe, Ross H.; Spargo, Erin A. Kolbrich; Milman, Garry; Pirnay, Stephane O.; Gorelick, David A.; Goodwin, Robert S.; Huestis, Marilyn A.

    2011-01-01

    3,4-Methylenedioxymethamphetamine (MDMA), or ecstasy, is excreted as unchanged drug, 3,4-methylenedioxyamphetamine (MDA), and free and glucuronidated/sulfated 4-hydroxy-3-methoxymethamphetamine (HMMA), and 4-hydroxy-3-methoxyamphetamine (HMA) metabolites. The aim of this paper is to describe the pattern and timeframe of excretion of MDMA and its metabolites in urine. Placebo, 1.0 mg/kg, and 1.6 mg/kg oral MDMA doses were administered double-blind to healthy adult MDMA users on a monitored research unit. All urine was collected, aliquots were hydrolyzed, and analytes quantified by gas chromatography–mass spectrometry. Median Cmax, Tmax, ratios, first and last detection times, and detection rates were determined. Sixteen participants provided 916 urine specimens. After 1.6 mg/kg, median Cmax were 21,470 (MDMA), 2229 (MDA), 20,793 (HMMA), and 876 ng/mL (HMA) at median Tmax of 13.9, 23.0, 9.2 and 23.3 h. In the first 24 h, 30.2–34.3% total urinary excretion occurred. HMMA last detection exceeded MDMA’s by more than 33 h after both doses. Identification of HMMA as well as MDMA increased the ability to identify positive specimens but required hydrolysis. These MDMA, MDA, HMMA, and HMA pharmacokinetic data may be useful for interpreting workplace, drug treatment, criminal justice, and military urine drug tests. Measurement of urinary HMMA provides the longest detection of MDMA exposure yet is not included in routine monitoring procedures. PMID:19874650

  18. Effects of opiates on sodium excretion in the isolated perfused rat kidney.

    PubMed

    Ellis, A G; Adam, W R

    1991-12-01

    1. A rat isolated perfused kidney preparation was utilized to define clearly a renal site of action. The variables measured were perfusate pressure and flow, glomerular filtration rate, urine volume, sodium excretion and potassium excretion. 2. Dextromethorphan (3 nmol/L) and dextrorphan (10 nmol/L) reduced sodium excretion in kidneys from rats on either control or high K+ diet, in the absence of any other measured renal effects. Dextromethorphan (10 nmol/L) produced a decrease in glomerular filtration rate as well as a decrease in sodium excretion. Naloxone (1 mumol/L) inhibited the effect of dextromethorphan on sodium excretion but had no effect when administered alone. 3. The levorotatory opiates levorphanol and levomethorphan, the kappa agonist ketocyclazocine and a range of other opiates had no effect on sodium excretion. 4. The results suggest a renal action specific for dextrorotatory opiates. This renal action is consistent with earlier binding studies suggesting preferential recognition of dextrorotatory opiates. PMID:1797448

  19. Absorption, distribution, metabolism and excretion of selenium following oral administration of elemental selenium nanoparticles or selenite in rats.

    PubMed

    Loeschner, Katrin; Hadrup, Niels; Hansen, Marianne; Pereira, Sonia A; Gammelgaard, Bente; Møller, Laura Hyrup; Mortensen, Alicja; Lam, Henrik Rye; Larsen, Erik H

    2014-02-01

    A suspension of nanoparticles of BSA-stabilized red amorphous elemental selenium (Se) or an aqueous solution of sodium selenite was repeatedly administered by oral gavage for 28 days at 0.05 mg kg(-1) bw per day (low dose) or at 0.5 mg kg(-1) bw per day (high dose) as Se to female rats. Prior to administration, the size distribution of the Se nanoparticles was characterized by dynamic light scattering and transmission electron microscopy, which showed that the particles' mean diameter was 19 nm and ranged in size from 10 to 80 nm. Following administration of the high dose of Se nanoparticles or selenite the concentration of Se was determined by ICP-MS in the liver, kidney, urine, feces, stomach, lungs, and plasma at the μg g(-1) level and in brain and muscle tissue at the sub-μg g(-1) level. In order to test if any elemental Se was present in the liver, kidney or feces, an in situ derivatization selective to elemental Se was performed by treatment with sulfite, which resulted in formation of the selenosulfate anion. This Se species was selectively and quantitatively determined by anion exchange HPLC and ICP-MS detection. The results showed that elemental Se was present in the livers, kidneys and feces of animals exposed to low and high doses of elemental Se nanoparticles or to selenite, and was also detected in the same samples from control animals. The fraction of Se present as elemental Se in livers and kidneys from the high dose animals was significantly larger than the similar fraction in samples from the low dose animals or from the controls. This suggested that the natural metabolic pathways of Se were exhausted when given the high dose of elemental Se or selenite resulting in a non-metabolized pool of elemental Se. Both dosage forms of Se were bioavailable as demonstrated by the blood biomarker selenoprotein P, which was equally up-regulated in the high-dose animals for both dosage forms of Se. Finally, the excretion of Se in urine and its occurrence as Se

  20. Effects of piretanide, bumetanide and frusemide on electrolyte and urate excretion in normal subjects.

    PubMed

    Roberts, C J; Homeida, M; Roberts, F; Bogie, W

    1978-08-01

    1. The pharmacological actions of a new short acting loop diuretic were investigated in nine healthy male subjects and compared with those of frusemide and bumetanide. Subjects received 6 mg piretanide/day, 40 mg frusemide/day or 1 mg bumetanide/day for a period of 1 week. 2. Comparison of effects following the first dose administered showed that 6 mg piretanide is of similar potency to 40 mg frusemide in terms of diuresis, natriuresis and kaliuresis but is less potent than 1 mg bumetanide. 3. All three diuretics caused a decrease in urate excretion and a rise in serum uric acid. 4. Piretanide was well tolerated. Further investigation is required to ascertain what clinical advantage it offers over frusemide and bumetanide. PMID:678389

  1. Azolimine: a nonsteroidal antagonist of the effects of mineralocorticoids on renal electrolyte excretion.

    PubMed

    Gussin, R Z; Ronsberg, M A; Stokey, E H; Cummings, J R

    1975-10-01

    Azolimine, CL 90,748, an imidazolidinone, displayed the capacity to antagonize the effects of mineralocorticoids on renal electrolyte excretion in several animal models. Although large doses of azolimine produced natriuresis in adrenalectomized rats in the absence of exogenous mineralocorticoid, its effectiveness was greater in the presence of a steroid agonist. However, in conscious dogs given an infusion of saline plus dextrose, azolimine was only effective when desoxycorticosterone (DCA) was administered. The drug, therefore, may not be a pure competitive antagonist of mineralocorticoid, but its greater efficacy in the presence of mineralocorticoid distinguishes it from noncompetitive mineralocorticoid antagonists as amiloride and triamterene. Azolimine significantly improved the urinary Na/K ratio when used in combination with thiazides, furosemide and other classical diuretics both in adrenalectomized, desoxycorticosterone-treated rats and in sodium-deficient rats. PMID:1181406

  2. Chylomicrons enhance endotoxin excretion in bile.

    PubMed Central

    Read, T E; Harris, H W; Grunfeld, C; Feingold, K R; Calhoun, M C; Kane, J P; Rapp, J H

    1993-01-01

    Chylomicrons prevent endotoxin toxicity and increase endotoxin uptake by hepatocytes. As a consequence, less endotoxin is available to activate macrophages, thereby reducing tumor necrosis factor secretion. To determine whether the chylomicron-mediated increase in hepatocellular uptake of endotoxin results in increased endotoxin excretion into bile, we examined bile after endotoxin administration. A sublethal dose (7 micrograms/kg) of 125I-endotoxin was incubated with either rat mesenteric lymph containing nascent chylomicrons (500 mg of chylomicron triglyceride per kg of body weight) or an equal volume of normal saline (controls) for 3 h and then infused into male Sprague-Dawley rats. Bile samples were collected via a common bile duct catheter for 24 h. Infusion of endotoxin incubated with chylomicrons increased biliary excretion of endotoxin by 67% at 3 h (P < or = 0.006) and by 20% at 24 h (P < or = 0.01) compared with infusion of endotoxin incubated in saline. Endotoxin activity, as measured by the Limulus assay, was not detected in the bile of test animals. However, endotoxin activity was detected after hot phenol-water extraction of bile, demonstrating that endotoxin is inactive in the presence of bile but retains bioactivity after hepatic processing. Since the majority of an intravenous endotoxin load has been shown to be cleared by the liver, acceleration of hepatocyte clearance and biliary excretion of endotoxin may represent a component of the mechanism by which chylomicrons protect against endotoxin-induced lethality. PMID:8335381

  3. Microbiological screening test validation for detection of tylosin excretion in milk of cows with low and high somatic cell counts.

    PubMed

    Litterio, N J; Calvinho, L F; Flores, M M; Tarabla, H D; Boggio, J C

    2007-02-01

    Antibiotic residues in milk above tolerance levels interfere with dairy product processing and pose potential health risks to consumers. Residue avoidance programmes include, among other components, the observance of withdrawal times indicated in label instructions. Persistence of antibiotics in milk following treatment is influenced by drug, dosage, route of administration, body weight and mammary gland health status. Compositional changes that take place during intramammary infection (IMI) can affect antibiotic excretion in milk, thus modifying milk withdrawal time. The objectives of this study were to validate sensitivity and specificity of a qualitative microbiological method (Charm AIM-96) to detect tylosin in bovine composite milk and to determine the influence of subclinical IMI in tylosin excretion following intramuscular administration. For test validation, two groups of approximately 120 cows were used; one received a single intramuscular injection of tylosin tartrate at a dose of 20 mg/kg, while the other group remained as untreated control. Test sensitivity and specificity were 100% and 94.1% respectively. To determine the influence of subclinical IMI in tylosin excretion, two groups of seven cows, one with somatic cell counts (SCC) < or =250 000 cells/ml and the other with SCC > or =900 000, were administered a single intramuscular injection of tylosin tartrate at a dose of 20 mg/kg. Milk samples were obtained every 12 h for 10 days following treatment. Milk tylosin excretion averaged between 5 and 9 days for cows with low and high SCC respectively (P < 0.0001). Compositional changes in cows with high SCC most likely affect the pharmacokinetic characteristics of tylosin, extending the presence of the antibiotic in milk, thus influencing milk withdrawal times. PMID:17359452

  4. Influence of dose on the pharmacokinetics of cefadroxil.

    PubMed

    Mariño, E L; Dominguez-Gil, A

    1980-11-01

    The pharmacokinetics of Cefadroxil have been studied in a crossover study involving 20 experiments in four healthy volunteers (19--24 years), after oral administration of five individual doses of 250, 500, 750, 1000 and 1500 mg of the antibiotic in capsules to each person. Plasma and urine concentrations of the antibiotic were determined microbiologically by a plate diffusion method. The antibiotic followed an open, single-compartment kinetic model. The plasma half-life was not significantly influenced by dose; the average was 1.438 +/- 0.220 h. The percentage of the antibiotic excreted in urine, too, was not significantly affected by the dose, being close to 80% of the quantity originally administered within 24 h. The values of Cmax and (AUC) increased linearly with the administered dose. PMID:7461017

  5. Administering Eye Medications.

    ERIC Educational Resources Information Center

    Morris, Sara; Michael, Nancy, Ed.

    This module on administering eye medications is intended for use in inservice or continuing education programs for persons who administer medications in long-term care facilities. Instructor information, including teaching suggestions, and a listing of recommended audiovisual materials and their sources appear first. A brief discussion follows of…

  6. Relationships between biomarkers of exposure and toxicokinetics in Fischer 344 rats and B6C3F{sub 1} mice administered single doses of acrylamide and glycidamide and multiple doses of acrylamide

    SciTech Connect

    Tareke, Eden; Twaddle, Nathan C.; McDaniel, L. Patrice; Churchwell, Mona I.; Young, John F.; Doerge, Daniel R. . E-mail: daniel.doerge@fda.hhs.gov

    2006-11-15

    Acrylamide (AA) is a widely studied industrial chemical that is neurotoxic, mutagenic to somatic and germ cells and carcinogenic in rodents. AA is also formed in many commonly consumed starchy foods during cooking. Our previous toxicokinetic investigations of AA and its important genotoxic metabolite, glycidamide (GA), in rodents showed that AA is highly bioavailable from oral routes of administration, is widely distributed to tissues and that the dietary route, in particular, favors metabolism to GA. Measurements of DNA adducts in many tissues supported the hypothesis that AA is carcinogenic in rodent bioassays through metabolism to GA. The current investigation describes the development and validation of methodology for measuring hemoglobin (Hb) adducts with AA and GA in the same rodents previously used for toxicokinetic and DNA adduct measurements. The goal was to investigate possible relationships between these circulating biomarkers of exposure and serum toxicokinetic parameters for AA and GA and tissue GA-DNA adducts in rodents from both single and repeated dosing with AA. Significant correlations were observed between GA-Hb and liver GA-DNA adducts for either single or multiple dosing regimens with AA. Using available GA-Hb adduct data, empirical and allometric relationships permitted estimation of liver DNA adducts in humans in the range of 0.06-0.3 adducts/10{sup 8} nucleotides. This approach may prove useful in extrapolating human cancer risks from findings in rodent bioassays.

  7. Absorption of magnesium from orally administered magnesium sulfate in man.

    PubMed

    Morris, M E; LeRoy, S; Sutton, S C

    1987-01-01

    The use of magnesium sulfate (Epsom salt) as a cathartic in patients with impaired renal function can lead to severe toxicity due to hypermagnesemia. Although toxicity is uncommon in healthy subjects, little is known concerning the extent of absorption of magnesium after a cathartic dose of magnesium sulfate. The bioavailability of magnesium following a large oral dose of magnesium sulfate in normal volunteers was examined in the present investigation. Baseline 24-hour urinary excretion rates of magnesium and creatinine were determined over 3 consecutive days in 6 healthy men. The oral administration of 13.9 g (56.5 mmoles) magnesium sulfate U.S.P., in 4 equal hourly increments, resulted in the urinary excretion (corrected for baseline excretion rate) of 4.0 +/- 2.9% (mean +/- SD) of the dose of magnesium during the first 24 hours and 6.9 +/- 7.0% of the dose during a 72-hour interval. Magnesium sulfate administration had no effect on the 24-hour urinary excretion rate of creatinine. The baseline excretion rate of magnesium was significantly correlated with that of creatinine (r = 0.875) and inorganic sulfate (r = 0.921). All of the subjects experienced mild or moderate diarrhea. Therefore, magnesium is absorbed to a limited and variable extent in healthy adults following a cathartic dose of magnesium sulfate. PMID:3430654

  8. Systemic absorption of endotracheally administered aminoglycosides in seriously ill patients with pneumonia.

    PubMed Central

    Crosby, S S; Edwards, W A; Brennan, C; Dellinger, E P; Bauer, L A

    1987-01-01

    A study was performed with 10 hospitalized patients to determine the percentage of an aminoglycoside dose (tobramycin or gentamicin) that is absorbed systemically after being instilled into the endotracheal tube at steady state. All patients were on respirators, had indwelling urinary catheters, and had creatinine clearances estimated to be greater than or equal to 40 ml/min. Tobramycin or gentamicin (40 mg) was instilled every 4 h directly into the endotracheal tube. Nine patients also received systemically a different aminoglycoside from that administered through the endotracheal tube. Urine was collected over a 4-h dosing interval at steady state (after at least 5 doses of the drug). The amount of aminoglycoside excreted over the 4-h interval was measured and expressed as percentage of the dose administered over that period. The range of percentage of dose absorbed was 1.5 to 34%, with a mean of 16.7 +/- 11.4% standard deviation and a median of 16.5%. The coefficient of variation was 68%. Levels of the endotracheally administered aminoglycoside in serum were measured, and all were less than 1.0 microgram/ml. While a large degree of variability in absorption was observed in this study, significant amounts of aminoglycosides could be absorbed in some patients. However, levels apparently did not accumulate in sera of patients with adequate renal function, and an empirical dosage reduction in intravenous aminoglycoside should not be necessary with the addition of endotracheally instilled aminoglycoside in patients with creatinine clearances greater than 40 ml/min. PMID:3619417

  9. Biliary excretion and intestinal metabolism of progesterone and estrogens in man.

    PubMed

    Adlercreutz, H; Martin, F

    1980-02-01

    The biliary excretion and intestinal metabolism (including intestinal mucosa and small intestine and bowel) of progesterone and estrogens in humans are reviewed here along with presentation of experimental results from other mammalian systems. In general, the biliary excretion of estrogens and the enterohepatic circulation of estrogen metabolites are more extensive than for progesterone. These processes may be of greater physiological importance because of the possible reformation of biologically active estrogens in the intestine, which occurs 2 ways: 1) by hydrolysis of biliary estrogen conjugates and absorption of the unconjugated estrogens which may partly reach general circulation, and 2) by production of biologically active estrogens from neutral steroids or less active estrogens in the intestinal tract, followed by absorption. Here, the kidneys also play a significant role in estrogen metabolism and conjugation. The quantitative contribution of liver, kidneys, and intestine to estrogen metabolism cannot be accurately assessed at present, but the liver and intestines probably play the most significant role, followed by the kidneys. Progesterone (from orally administered doses) and its metabolites are extensively metabolized in the intestine to compounds with less progestational activity; hence, synthetic progestins may alter the intestinal flora which in turn may influence the plasma levels of these compounds. On these subjects more research in indicated. PMID:6991820

  10. Effect of levitra on sustenance of erection (EROS): an open-label, prospective, multicenter, single-arm study to investigate erection duration measured by stopwatch with flexible dose vardenafil administered for 8 weeks in subjects with erectile dysfunction.

    PubMed

    Shin, Y S; Lee, S W; Park, K; Chung, W S; Kim, S W; Hyun, J S; Moon, D G; Yang, S-K; Ryu, J K; Yang, D Y; Moon, K H; Min, K S; Park, J K

    2015-01-01

    To investigate the change of erection duration measured by stopwatch with flexible dose vardenafil administered for 8 weeks in subjects with erectile dysfunction (ED). Effect of levitra on sustenance of erection was an open-label, prospective, multicenter and single-arm study designed to measure the duration of erection in men with ED receiving a flexible dose of vardenafil over an 8-week treatment period. Patients were instructed to take vardenafil 10 mg 60 min before attempting the intercourse. Vardenfil could be increased to 20 mg or decreased to 5 mg concerning patients' efficacy and safety. Following the initial screening, patients entered a 4-week treatment-free run-in phase and 8-week treatment period, during which they were instructed to attempt intercourse at least four times on four separate days. A total of 95 men were enrolled in 10 centers. After the 8 weeks treatment, the mean duration of erection leading to successful intercourse was statistically superior when patients were treated with vardenafil. After an 8-week treatment, the duration of erection leading to successful intercourse was 9.39 min. There were significant benefits with vardenafil in all domains of International Index of Erectile Function. Secondary efficacy end points included success rate of penetration, maintaining erection, ejaculation and satisfaction were superior when patients were treated with vardenafil. There was a significant correlation between duration of erection with other sexual factors. Also partner's sexual satisfaction was increased with vardenafil. Most adverse events were mild or moderate in severity. Vardenafil was safe and well tolerated. Vardenafil therapy provided a statistically superior duration of erection leading to successful intercourse in men with ED with female partner. PMID:25471318

  11. Absorption, distribution, metabolism, and excretion of [14C]-labeled naloxegol in healthy subjects

    PubMed Central

    Bui, Khanh; She, Fahua; Hutchison, Michael; Brunnström, Åsa; Sostek, Mark

    2015-01-01

    Objective: To characterize the absorption, distribution, metabolism, and excretion of naloxegol, a PEGylated derivative of the µ-opioid antagonist naloxone, in healthy male subjects. Materials and methods: [14C]-Labeled naloxegol (27 mg, 3.43 MBq) was administered as an oral solution to 6 fasted subjects. Blood, fecal, and urine samples were collected predose and at various intervals postdose. Naloxegol and its metabolites were quantified or identified by liquid chromatography with radiometric or mass spectrometric detection. Pharmacokinetic parameters were calculated for each subject, and metabolite identification was performed by liquid chromatography with parallel radioactivity measurement and mass spectrometry. Results: Naloxegol was rapidly absorbed, with a maximum plasma concentration (geometric mean) of 51 ng/mL reached before 2 hours after dosing. A second peak in the observed naloxegol and [14C] plasma concentration-time profiles was observed at ~ 3 hours and was likely due to enterohepatic recycling of parent naloxegol. Distribution to red blood cells was negligible. Metabolism of [14C]-naloxegol was rapid and extensive and occurred via demethylation and oxidation, dealkylation, and shortening of the polyethylene glycol chain. Mean cumulative recovery of radioactivity was 84.2% of the total dose, with ~ 68.9% recovered within 96 hours of dosing. Fecal excretion was the predominant route of elimination, with mean recoveries of total radioactivity in feces and urine of 67.7% and 16.0%, respectively. Unchanged naloxegol accounted for ~ 1/4 of the radioactivity recovered in feces. Conclusions: Naloxegol was rapidly absorbed and cleared via metabolism, with predominantly fecal excretion of parent and metabolites. PMID:26329350

  12. Semi-micro column high-performance liquid chromatography with UV detection for quantification of aspirin and salicylic acid and its application to patients' sera administered with low-dose enteric-coated aspirin.

    PubMed

    Ohwaki, Yuichi; Yamane, Tomoko; Ishimatsu, Takashi; Wada, Mitsuhiro; Nakashima, Kenichiro

    2007-03-01

    A simultaneous determination of aspirin (ASA) and its metabolite, salicylic acid (SA), in human serum by a semi-micro column HPLC-UV was developed. A relatively small size of serum sample (100 microL) containing ASA and SA was cleaned up by a simple solid phase extraction. A good separation of ASA and SA could be achieved within 25 min using a semi-micro ODS column with an eluent of MeOH/0.7 mm phosphoric acid solution (pH 2.5) = 50:50 (v/v). The calibration curves for ASA and SA showed good linearity (r = 0.999) with the detection limits 114 and 38 ng/mL at a signal-to-noise ratio of 3, respectively. ASA and SA in patients' sera administered with low-dose enteric-coated aspirin were determined, and the concentration ranges obtained for ASA and SA were 1.2-2.2 and 0.5-57.3 microg/mL, respectively. PMID:17221906

  13. Purine derivative excretion in dairy cows: endogenous excretion and the effect of exogenous nucleic acid supply.

    PubMed

    Gonzalez-Ronquillo, M; Balcells, J; Guada, J A; Vicente, F

    2003-04-01

    An experiment was conducted with dairy cows to study the partitioning of excreted purine derivatives between urine and milk and to quantify the endogenous contribution following the isotopic labeling of microbial purine bases. Three lactating cows in their second lactation that had been cannulated in the rumen and the duodenum were fed a mixed diet (48:52, roughage/concentrate ratio) distributed in equal fractions every 2 h, and duodenal flow of purine bases was determined by the dual-phase marker system. Nitrogen-15 was infused continuously into the rumen to label microbial purine bases, and the endogenous fraction was determined from the isotopic dilution in urinary purine derivatives. Urinary and milk recovery of duodenal purine bases were estimated at early (wk 10) and late (wk 33) lactation by the duodenal infusion of incremental doses (75 and 150 mmol purine bases/d) of RNA from Torula yeast. Each period was 6 d, with RNA being infused during the last 4 d, followed by measurement of the flow of purine bases to the duodenum. The isotope dilution of purine derivatives in urine samples confirmed the presence of an endogenous fraction (512 +/- 36.43 micromol/W0.75 or 56.86 mmol/d) amounting to 26 +/- 3.8% of total renal excretion. Total excretion of purine derivatives in urine plus milk was linearly related to the duodenal input of purine bases, but the slopes differed (P < 0.005) between lactation stages resulting in a lower equimolar recovery in early (y = 58.86 (+/-3.89) +0.56 (+/-0.0164) x; r = 0.90) than late lactation (y = 58.86 (+/-3.89) + 0.70 (+/-0.046) x; r = 0.80). Excretion of purine derivatives through milk represented a minimum fraction of total excretion but responded significantly to the duodenal input of purine bases. No differences between lactation stages were detected, and variations in milk yield did modify significantly the amount of purine derivatives excreted through the milk. PMID:12741553

  14. Orally administered DTPA penta-ethyl ester for the decorporation of inhaled 241Am

    PubMed Central

    Sueda, Katsuhiko; Sadgrove, Matthew P.; Huckle, James E.; Leed, Marina G. D.; Weber, Waylon M.; Doyle-Eisele, Melanie; Guilmette, Raymond A.; Jay, Michael

    2014-01-01

    Diethylenetriaminepentaacetic acid (DTPA) is an effective decorporation agent to facilitate the elimination of radionuclides from the body, but its permeability-limited oral bioavailability limits its utility in mass-casualty emergencies. To overcome this limitation, a prodrug strategy using the penta-ethyl ester form of DTPA is under investigation. Pharmacokinetic and biodistribution studies were conducted in rats by orally administering [14C]DTPA penta-ethyl ester, and this prodrug and its hydrolysis products were analyzed as a single entity. Compared to a previous reporting of intravenously administered DTPA, the oral administration of this prodrug resulted in a sustained plasma concentration profile with higher plasma exposure and lower clearance. An assessment of the urine composition revealed that the bioactivation was extensive but incomplete, with no detectable levels of the penta- or tetra-ester forms. Tissue distribution at 12 h was limited, with approximately 73% of the administered dose being associated with the gastrointestinal tract. In the efficacy study, rats were exposed to aerosols of 241Am nitrate before receiving a single oral treatment of the prodrug. The urinary excretion of 241Am was found to be 19% higher than with the control. Consistent with prior reports of DTPA, the prodrug was most effective when the treatment delays were minimized. PMID:24619514

  15. Orally administered DTPA penta-ethyl ester for the decorporation of inhaled (241)Am.

    PubMed

    Sueda, Katsuhiko; Sadgrove, Matthew P; Huckle, James E; Leed, Marina G D; Weber, Waylon M; Doyle-Eisele, Melanie; Guilmette, Raymond A; Jay, Michael

    2014-05-01

    Diethylenetriaminepentaacetic acid (DTPA) is an effective decorporation agent to facilitate the elimination of radionuclides from the body, but its permeability-limited oral bioavailability limits its utility in mass-casualty emergencies. To overcome this limitation, a prodrug strategy using the penta-ethyl ester form of DTPA is under investigation. Pharmacokinetic and biodistribution studies were conducted in rats by orally administering [(14) C]DTPA penta-ethyl ester, and this prodrug and its hydrolysis products were analyzed as a single entity. Compared with a previous reporting of intravenously administered DTPA, the oral administration of this prodrug resulted in a sustained plasma concentration profile with higher plasma exposure and lower clearance. An assessment of the urine composition revealed that the bioactivation was extensive but incomplete, with no detectable levels of the penta- or tetra-ester forms. Tissue distribution at 12 h was limited, with approximately 73% of the administered dose being associated with the gastrointestinal tract. In the efficacy study, rats were exposed to aerosols of (241) Am nitrate before receiving a single oral treatment of the prodrug. The urinary excretion of (241) Am was found to be 19% higher than with the control. Consistent with prior reports of DTPA, the prodrug was most effective when the treatment delays were minimized. PMID:24619514

  16. Ammonia excretion by Azobacter chroococcum

    SciTech Connect

    Narula, N.; Lakshminarayana, K.; Tauro, P.

    1981-02-01

    In recent years, research has focused attention on the development of biological systems for nitrogen fixation. In this report, two strains of Azotobacter chroococcum are identified which can excrete as much as 45 mg ammonia/ml of the culture broth in a sucrose supplemented synthetic medium.

  17. Benzo(a)pyrenediolepoxide-hemoglobin adducts and 3-hydroxy-benzo(a)pyrene urinary excretion profiles in rats subchronically exposed to benzo(a)pyrene.

    PubMed

    Bouchard, M; Viau, C

    1995-01-01

    The time profiles of benzo(a)pyrenediolepoxide (BaPDE)-hemoglobin (Hb) adduct formation and 3-hydroxybenzo(a)pyrene (3-OHBaP) urinary excretion were studied in male Sprague-Dawley rats exposed to daily benzo(a)pyrene (BaP) intraperitoneal doses of 1.25, 6.25, and 31.25 mumol/kg administered Tuesday to Friday for 4 consecutive weeks. Blood was withdrawn weekly, on Tuesdays, prior to dosing. Twenty-four-hour urine samples were collected on Mondays (following 72 h without treatment) and Thursdays. Analytes were quantified by high performance liquid chromatography (HPLC)/fluorescence. Exposure to BaP resulted in the accumulation of BaPDE-Hb adducts, reaching an average of 1.2 +/- 0.3, 8.3 +/- 1.9, and 38.2 +/- 6.1 pmol/g Hb for the 1.25, 6.25, and 31.25 mumol/kg per day doses after 4 weeks of treatment. The expected saw tooth excretion profile of 3-OHBaP was observed, with peaks on Thursdays and troughs on Mondays, and showed a progressive rise on both Mondays and Thursdays. Increase in Monday values with time suggested a possible increase in BaP body burden during exposure. To verify this aspect further, the urinary excretion kinetic of 3-OHBaP following acute intraperitoneal dosing (31.25 mumol/kg) was determined. Urine samples were collected at frequent timed intervals for up to 164 h post-dosing. Two-step elimination was observed, the second step having a half-life of 25 h, presumably linked to the slow release of BaP accumulated in fatty tissues upon repeated treatment.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8534197

  18. Sustained immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine administered as a two-dose schedule in adolescent girls: Five-year clinical data and modeling predictions from a randomized study

    PubMed Central

    Romanowski, Barbara; Schwarz, Tino F; Ferguson, Linda; Peters, Klaus; Dionne, Marc; Behre, Ulrich; Schulze, Karin; Hillemanns, Peter; Suryakiran, Pemmaraju; Thomas, Florence; Struyf, Frank

    2016-01-01

    In this randomized, partially-blind study (clinicaltrials.gov; NCT00541970), the licensed formulation of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (20 μg each of HPV-16/18 antigens) was found highly immunogenic up to 4 y after first vaccination, whether administered as a 2-dose (2D) schedule in girls 9–14 y or 3-dose (3D) schedule in women 15–25 y. This end-of-study analysis extends immunogenicity and safety data until Month (M) 60, and presents antibody persistence predictions estimated by piecewise and modified power law models. Healthy females (age stratified: 9–14, 15–19, 20–25 y) were randomized to receive 2D at M0,6 (N = 240 ) or 3D at M0,1,6 (N = 239). Here, results are reported for girls 9–14 y (2D) and women 15–25 y (3D). Seropositivity rates, geometric mean titers (by enzyme-linked immunosorbent assay) and geometric mean titer ratios (GMRs; 3D/2D; post-hoc exploratory analysis) were calculated. All subjects seronegative pre-vaccination in the according-to-protocol immunogenicity cohort were seropositive for anti-HPV-16 and −18 at M60. Antibody responses elicited by the 2D and 3D schedules were comparable at M60, with GMRs close to 1 (anti-HPV-16: 1.13 [95% confidence interval: 0.82–1.54]; anti-HPV-18: 1.06 [0.74–1.51]). Statistical modeling predicted that in 95% of subjects, antibodies induced by 2D and 3D schedules could persist above natural infection levels for ≥ 21 y post-vaccination. The vaccine had a clinically acceptable safety profile in both groups. In conclusion, a 2D M0,6 schedule of the HPV-16/18 AS04-adjuvanted vaccine was immunogenic for up to 5 y in 9–14 y-old girls. Statistical modeling predicted that 2D-induced antibodies could persist for longer than 20 y. PMID:26176261

  19. Single-Dose Pharmacokinetics of Methylphenidate Extended-Release Multiple Layer Beads Administered as Intact Capsule or Sprinkles Versus Methylphenidate Immediate-Release Tablets (Ritalin®) in Healthy Adult Volunteers

    PubMed Central

    Teuscher, Nathan S.; Kupper, Robert J.; Chang, Wei-Wei; Greenhill, Laurence; Newcorn, Jeffrey H.; Connor, Daniel F.; Wigal, Sharon

    2014-01-01

    Abstract Objectives: The purpose of this study was to evaluate the relative bioavailability and safety of a multilayer extended-release bead methylphenidate (MPH) hydrochloride 80 mg (MPH-MLR) capsule or sprinkles (37% immediate-release [IR]) versus MPH hydrochloride IR(Ritalin®) tablets, and to develop a pharmacokinetic (PK) model simulating MPH concentration-time data for different MPH-MLR dosage strengths. Methods: This was a single-center, randomized, open-label, three-period crossover study conducted in 26 fasted healthy adults (mean weight±standard deviation, 70.4±11.7 kg) assigned to single-dose oral MPH-MLR 80 mg capsule or sprinkles with applesauce, or Ritalin IR 25 mg (1×5 mg and 1×20 mg tablet) administered at 0, 4, and 8 hours. Results: MPH-MLR 80 mg capsule and sprinkles were bioequivalent; ratios for maximum concentration (Cmax), area under plasma drug concentration versus time curve (AUC)0-t, and AUC0-inf were 1.04 (95% confidence interval [CI], 96.3–112.4), 0.99 (95% CI, 95.3–102.8), and 0.99 (95% CI, 95.4–103.0), respectively. MPH-MLR capsule/sprinkles produced highly comparable, biphasic profiles of plasma MPH concentrations characterized by rapid initial peak, followed by moderate decline until 5 hours postdose, and gradual increase until 7 hours postdose, culminating in an attenuated second peak. Based on 90% CIs, total systemic exposure to MPH-MLR 80 mg capsule/sprinkles was similar to that for Ritalin IR 25 mg three times daily, but marked differences in Cmax values indicated that MPH-MLR regimens were not bioequivalent to Ritalin. MPH Cmax and total systemic exposure over the first 4 hours postdose with MPH-MLR capsule/sprinkles was markedly higher than that associated with the first dose of Ritalin. All study drugs were safe and well tolerated. The PK modeling in adults suggested that differences in MPH pharmacokinetics between MPH-MLR and Ritalin are the result of dosage form design attributes and the associated

  20. Pre-therapeutic 124I PET(/CT) dosimetry confirms low average absorbed doses per administered 131I activity to the salivary glands in radioiodine therapy of differentiated thyroid cancer

    PubMed Central

    Hobbs, Robert F.; Stahl, Alexander; Knust, Jochen; Sgouros, George; Bockisch, Andreas

    2010-01-01

    Purpose Salivary gland impairment following high activity radioiodine therapy of differentiated thyroid cancer (DTC) is a severe side effect. Dosimetric calculations using planar gamma camera scintigraphy (GCS) with 131I and ultrasonography (US) provided evidence that the average organ dose per administered 131I activity (ODpA) is too low to account for observed radiation damages to the salivary glands. The objective of this work was to re-estimate the ODpA using 124I PET(/CT) as a more reliable approach than 131I GCS/US. Methods Ten DTC patients underwent a series of six (or seven) PET scans and one PET/CT scan after administration of ~23 MBq 124I-iodide. Volumes of interest (VOIs) drawn on the CT and serial PET images were used to determine the glandular volumes and the imaged 124I activities. To enable identical VOIs to be drawn on serial PET images, each PET was co-registered with the CT image. To correct for partial volume effect and for the artificial bias in the activity concentration due to cascading gamma coincidences occurring in 124I decay, the imaged activity was effectively corrected using isovolume recovery coefficients (RCs) based on recovery phantom measurements. A head-neck phantom, which contained 124I-filled spheres, was manufactured to validate the isovolume recovery correction method with a realistic patient-based phantom geometry and for a range of activity concentration regimes. The mean±standard deviation (range) ODpA projected for 131I was calculated using the absorbed dose fraction method. Results The ODpAs (in Gy/GBq) for the submandibular and parotid glands were 0.32±0.13 (0.18–0.55) and 0.31±0.10 (0.13–0.46), respectively. No significant differences (p>0.2) in the mean ODpA between 124I PET(/CT) and 131I GCS/US dosimetry was found. The validation experiment showed that the percentage deviations between RC-corrected and true activity concentrations were <10%. Conclusion 124I PET(/CT) dosimetry also corroborates the low ODpAs to

  1. Alpha- and gamma-tocotrienols are metabolized to carboxyethyl-hydroxychroman derivatives and excreted in human urine.

    PubMed

    Lodge, J K; Ridlington, J; Leonard, S; Vaule, H; Traber, M G

    2001-01-01

    Limited information is available regarding metabolism of vitamin E forms, especially the tocotrienols. Carboxyethyl-hydroxychromans (alpha- and gamma-CEHC) are human urinary metabolites of alpha- and gamma-tocopherols, respectively. To evaluate whether tocotrienols are also metabolized and excreted as urinary CEHC, urine was monitored following tocotrienol supplementation. Complete (24 h) urine collections were obtained for 2 d prior to (baseline), the day of, and 2 d after human subjects (n = 6) ingested tocotrienol supplements. The subjects consumed 125 mg gamma-tocotrienyl acetate the first week, then the next week 500 mg; then 125 mg alpha-tocotrienyl acetate was administered the third week, followed by 500 mg the fourth week. Urinary alpha- and gamma-CEHC were measured by high-performance liquid chromatography with electrochemical detection. Urinary gamma-CEHC levels rose about four- to sixfold in response to the two doses of gamma-tocotrienol and then returned to baseline the following day. Significant (P < 0.0001) increases in urinary alpha-CEHC were observed only following ingestion of 500 mg alpha-tocotrienyl acetate. Typically, 1-2% of alpha-tocotrienyl acetates or 4-6% of gamma-tocotrienyl acetates were recovered as their respective urinary CEHC metabolites. A gamma-CEHC excretion time course showed an increase in urinary gamma-CEHC at 6 h and a peak at 9 h following ingestion of 125 mg gamma-tocotrienyl acetate. In summary, tocotrienols, like tocopherols, are metabolized to CEHC; however, the quantities excreted in human urine are small in relation to dose size. PMID:11214728

  2. Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine

    PubMed Central

    Sparreboom, Alex; van Asperen, Judith; Mayer, Ulrich; Schinkel, Alfred H.; Smit, Johan W.; Meijer, Dirk K. F.; Borst, Piet; Nooijen, Willem J.; Beijnen, Jos H.; van Tellingen, Olaf

    1997-01-01

    In mice, the mdr1a and mdr1b genes encode drug-transporting proteins that can cause multidrug resistance in tumor cells by lowering intracellular drug levels. These P-glycoproteins are also found in various normal tissues such as the intestine. Because mdr1b P-glycoprotein is not detectable in the intestine, mice with a homozygously disrupted mdr1a gene [mdr1a(−/−) mice] do not contain functional P-glycoprotein in this organ. We have used these mdr1a(−/−) mice to study the effect of gut P-glycoprotein on the pharmacokinetics of paclitaxel. The area under the plasma concentration-time curves was 2- and 6-fold higher in mdr1a(−/−) mice than in wild-type (wt) mice after i.v. and oral drug administration, respectively. Consequently, the oral bioavailability in mice receiving 10 mg paclitaxel per kg body weight increased from only 11% in wt mice to 35% in mdr1a(−/−) mice. The cumulative fecal excretion (0–96 hr) was markedly reduced from 40% (after i.v. administration) and 87% (after oral administration) of the administered dose in wt mice to below 3% in mdr1a(−/−) mice. Biliary excretion was not significantly different in wt and mdr1a(−/−) mice. Interestingly, after i.v. drug administration of paclitaxel (10 mg/kg) to mice with a cannulated gall bladder, 11% of the dose was recovered within 90 min in the intestinal contents of wt mice vs. <3% in mdr1a(−/−) mice. We conclude that P-glycoprotein limits the oral uptake of paclitaxel and mediates direct excretion of the drug from the systemic circulation into the intestinal lumen. PMID:9050899

  3. Comparison of endogenous and radiolabeled bile acid excretion in patients with idiopathic chronic diarrhea

    SciTech Connect

    Schiller, L.R.; Bilhartz, L.E.; Santa Ana, C.A. )

    1990-04-01

    Fecal recovery of radioactivity after ingestion of a bolus of radiolabeled bile acid is abnormally high in most patients with idiopathic chronic diarrhea. To evaluate the significance of this malabsorption, concurrent fecal excretion of both exogenous radiolabeled bile acid and endogenous (unlabeled) bile acid were measured in patients with idiopathic chronic diarrhea. Subjects received a 2.5-microCi oral dose of taurocholic acid labeled with 14C in the 24th position of the steroid moiety. Endogenous bile acid excretion was measured by a hydroxysteroid dehydrogenase assay on a concurrent 72-h stool collection. Both radiolabeled and endogenous bile acid excretion were abnormally high in most patients with chronic diarrhea compared with normal subjects, even when equivoluminous diarrhea was induced in normal subjects by ingestion of osmotically active solutions. The correlation between radiolabeled and endogenous bile acid excretion was good. However, neither radiolabeled nor endogenous bile acid excretion was as abnormal as is typically seen in patients with ileal resection, and none of these diarrhea patients responded to treatment with cholestyramine with stool weights less than 200 g. These results suggest (a) that this radiolabeled bile acid excretion test accurately reflects excess endogenous bile acid excretion; (b) that excess endogenous bile acid excretion is not caused by diarrhea per se; (c) that spontaneously occurring idiopathic chronic diarrhea is often associated with increased endogenous bile acid excretion; and (d) that bile acid malabsorption is not likely to be the primary cause of diarrhea in most of these patients.

  4. African Swine Fever Virus Georgia 2007 with a Deletion of Virulence-Associated Gene 9GL (B119L), when Administered at Low Doses, Leads to Virus Attenuation in Swine and Induces an Effective Protection against Homologous Challenge

    PubMed Central

    O'Donnell, Vivian; Holinka, Lauren G.; Krug, Peter W.; Gladue, Douglas P.; Carlson, Jolene; Sanford, Brenton; Alfano, Marialexia; Kramer, Edward; Lu, Zhiqiang; Arzt, Jonathan; Reese, Bo; Carrillo, Consuelo; Risatti, Guillermo R.

    2015-01-01

    ABSTRACT African swine fever virus (ASFV) is the etiological agent of an often lethal disease of domestic pigs. Disease control strategies have been hampered by the unavailability of vaccines against ASFV. Since its introduction in the Republic of Georgia, a highly virulent virus, ASFV Georgia 2007 (ASFV-G), has caused an epizootic that spread rapidly into Eastern European countries. Currently no vaccines are available or under development to control ASFV-G. In the past, genetically modified ASFVs harboring deletions of virulence-associated genes have proven attenuated in swine, inducing protective immunity against challenge with homologous parental viruses. Deletion of the gene 9GL (open reading frame [ORF] B119L) in highly virulent ASFV Malawi-Lil-20/1 produced an attenuated phenotype even when administered to pigs at 106 50% hemadsorption doses (HAD50). Here we report the construction of a genetically modified ASFV-G strain (ASFV-G-Δ9GLv) harboring a deletion of the 9GL (B119L) gene. Like Malawi-Lil-20/1-Δ9GL, ASFV-G-Δ9GL showed limited replication in primary swine macrophages. However, intramuscular inoculation of swine with 104 HAD50 of ASFV-G-Δ9GL produced a virulent phenotype that, unlike Malawi-Lil-20/1-Δ9GL, induced a lethal disease in swine like parental ASFV-G. Interestingly, lower doses (102 to 103 HAD50) of ASFV-G-Δ9GL did not induce a virulent phenotype in swine and when challenged protected pigs against disease. A dose of 102 HAD50 of ASFV-G-Δ9GLv conferred partial protection when pigs were challenged at either 21 or 28 days postinfection (dpi). An ASFV-G-Δ9GL HAD50 of 103 conferred partial and complete protection at 21 and 28 dpi, respectively. The information provided here adds to our recent report on the first attempts toward experimental vaccines against ASFV-G. IMPORTANCE The main problem for controlling ASF is the lack of vaccines. Studies on ASFV virulence lead to the production of genetically modified attenuated viruses that induce

  5. Predicting nitrogen excretion from cattle.

    PubMed

    Reed, K F; Moraes, L E; Casper, D P; Kebreab, E

    2015-05-01

    Manure nitrogen (N) from cattle production facilities can lead to negative environmental effects, such as contribution to greenhouse gas emissions, leaching and runoff to aqueous ecosystems leading to eutrophication, and acid rain. To mitigate these effects and to improve the efficiency of N use, accurate prediction of N excretion and secretions are required. A genetic algorithm was implemented to select models to predict fecal, urinary, and total manure N excretions, and milk N secretions from 3 classes of animals: lactating dairy cows, heifers and dry cows, and steers. Two tiers of model classes were developed for each category of animals based on model input requirements. A total of 6 models for heifers and dry cows and steers and an additional 2 models for lactating dairy cattle were developed. Evaluation of the models using K-fold cross validation based on all data and using the most recent 6 yr of data showed better prediction for total manure N and fecal N compared with urinary N excretion, which was the most variable response in the database. Compared with extant models from the literature, the models developed in this study resulted in a significant improvement in prediction error for fecal and urinary N excretions from lactating cows. For total manure production by lactating cows, extant and new models were comparable in their prediction ability. Both proposed and extant models performed better than the prediction methods used by the US Environmental Protection Agency for the national inventory of greenhouse gases. Therefore, the proposed models are recommended for use in estimation of manure N from various classes of animals. PMID:25747829

  6. Disposition of 2,4-dichlorophenoxyacetic acid dimethylamine by Fischer 344 rats dosed orally and dermally

    SciTech Connect

    Pelletier, O.; Ritter, L.; Caron, J.; Somers, D. )

    1989-01-01

    The dimethylamine salt of 14C-ring-labeled 2,4-D was administered to Fischer 344 rats orally (1 and 0.4 mg/kg body weight) and dermally (10 mg/kg body weight). Absorption, distribution, and elimination were determined from 14C-labeled 2,4-D in blood, tissues, and excreta. Quantitatively, most of the orally administered dose (94-96%) became systemically available within 6 h. Following dermal administration 10% of the dose became systemically available over 72 h. However, peak concentrations in blood and kidneys were achieved within 30 min of dosing by either route. By 1.5 h after dosing, 2,4-D concentrations in blood, muscle, liver, and kidneys had decreased in both the orally dosed and dermally dosed animals. Between 2 and 8 h, the blood, muscle, liver and kidney concentrations in dermally dosed animals maintained a plateau while urinary excretion increased, presumably due to continued absorption of 2,4-D from the skin. The concentrations in orally dosed animals continued to decrease. Following 7 h of dermal exposure, skin cleansing removed about 63% of the applied dose; about 17% of the applied dose remained at the site of dermal dosing. At 8 h, 2,4-D concentrations in blood, muscle, liver, and kidneys of dermally dosed animals began to decrease, most likely a result of the removal of the reservoir on the skin. However, 2,4-D continued to be absorbed from skin site, resulting in a slower decline of the 2,4-D concentrations in these tissues over remainder of the 72-h study period. By comparison, in animals that had been orally dosed, the absorbed dose was almost completely excreted within 24 h.

  7. LC-MS/MS determination and urinary excretion study of seven alkaloids in healthy Chinese volunteers after oral administration of Shuanghua Baihe tablets.

    PubMed

    Cheng, Minlu; Liu, Ruijuan; Wu, Yao; Gu, Pan; Zheng, Lu; Liu, Yujie; Ma, Pengcheng; Ding, Li

    2016-01-25

    An LC-MS/MS method was developed and validated for the simultaneous determination of magnoflorine, berberrubine, jatrorrhizine, coptisine, epiberberine, palmatine and berberine in human urine. The sample preparation procedure involved the four-fold dilution of the urine samples with acetonitrile/water (1:3, v/v). The chromatographic separation was achieved on a Hedera ODS-2 column under gradient elution at a flow rate of 0.4 mL/min with acetonitrile and water containing 0.5% formic acid as the mobile phase. The mass detection was performed in the positive mode. Calibration curves of the seven alkaloids showed good linearity (correlation coefficients>0.9973) over their concentration ranges. To meet the requirements of urinary excretion study for each alkaloid in human, the lower limit of quantification was set at different values from 0.05063 ng/mL to 2.034 ng/mL for the seven alkaloids, respectively. The intra- and inter-batch precision and accuracy were all within ± 15%. No matrix effect was observed for the analytes. The validated method was applied to the excretion study for the seven alkaloids in healthy Chinese volunteers after oral administration of Shuanghua Baihe tablets. The average 72 h cumulative urinary excretion of magnoflorine, berberrubine, jatrorrhizine, coptisine, epiberberine, palmatine and berberine accounted for 1.81%, 0.27%, 0.29%, 0.046%, 0.027%, 0.010% and 0.021% of the respective administered dose. PMID:26519688

  8. Assessment of fetal exposure risk following seminal excretion of a therapeutic IgG4 (T-IgG4) monoclonal antibody using a rabbit model.

    PubMed

    Breslin, William J; Hilbish, Kim G; Page, Todd J; Coutant, David E

    2014-09-01

    Studies were conducted in New Zealand White rabbits to assess the seminal transfer, vaginal absorption, and placental transfer of a therapeutic monoclonal antibody (T-IgG4). T-IgG4 was administered by intravenous injection (IV) in males and by IV and intravaginal routes in females. Low levels of T-IgG4 were excreted into seminal plasma (100- to 370-fold lower than serum concentrations) and absorbed following vaginal dosing (three orders of magnitude lower than IV administration). On gestation day 29 (GD29), fetal serum T-IgG4 levels were 1.5-fold greater than maternal levels following IV dosing. The fetal T-IgG4 exposure ratio for seminal transfer vs. direct maternal IV dosing was estimated to be 1.3×10(-8). Applying human serum T-IgG4 exposure data to the model, the estimated human T-IgG4 serum concentration from seminal transfer was 3.07×10(-7)μg/mL, an exposure level at least 1000-fold lower than the T-IgG4-ligand dissociation constant (Kd) and at least seven orders of magnitude lower than the in vivo concentration producing 20% inhibition of the target (EC20). These data indicate that excretion of a T-IgG4 into semen would not result in a biologically meaningful exposure risk to the conceptus of an untreated partner. PMID:24863471

  9. Aminothiol Receptors for Decorporation of Intravenously Administered 60Co in the Rat

    SciTech Connect

    Levitskaia, Tatiana G.; Morris, James E.; Creim, Jeffrey A.; Woodstock, Angela D.; Luders, Teresa; Curry, Terry L.; Thrall, Karla D.

    2010-01-01

    The reported investigation provides a comparison of the oral decorporation efficacy of L-glutathione (GSH), L-cysteine (Cys), and a liposomal GSH formulation (ReadiSorb) toward systemic cobalt-60 (60Co) to that observed following intravenous administration of GSH and Cys in F344 rats. L-histidine (His) was tested intravenously to compare in vivo efficacy of the aminothiol GSH and Cys chelators with that of aminoimidazole (His) chelator. 60Co was administered to animals by intravenous injection, followed by intravenous or oral gavage doses of a chelator repeated at 24 hour intervals for a total of 5 doses. The results suggest that GSH and Cys are potent decorporation agents for 60Co in the rat model, although the efficacy of treatment depends largely on systemic availability of a chelator. The intravenous GSH or Cys were most effective in reducing tissue 60Co levels and in increasing excretion of radioactivity compared to control animals. Liposomal encapsulation was found to markedly enhance the oral bioavailability of GSH compared to non-formulated GSH. Oral administration of ReadiSorb reduced 60Co levels in nearly all tissues by 12-43% compared to that observed for non-formulated GSH. Efficacy of oral Cys was only slightly reduced in comparison with intravenous Cys. Further studies to optimize the dosing regimen in order to maximize decorporation efficiency are warranted.

  10. Aminothiol receptors for decorporation of intravenously administered (60)Co in the rat.

    PubMed

    Levitskaia, Tatiana G; Morris, James E; Creim, Jeffrey A; Woodstock, Angela D; Luders, Teresa; Curry, Terry L; Thrall, Karla D

    2010-01-01

    This report provides a comparison of the oral decorporation efficacy of L-glutathione (GSH), L-cysteine (Cys), and a liposomal GSH formulation (ReadiSorb) toward systemic (60)Co to that observed following intravenous administration of GSH and Cys in F344 rats. Aminoacid L-histidine (His) containing no thiol functionality was tested intravenously to compare in vivo efficacy of the aminothiol (GSH, Cys) chelators with that of the aminoimidazole (His) chelator. In these studies, (60)Co was administered to animals by intravenous injection, followed by intravenous or oral gavage doses of a chelator repeated at 24-h intervals for a total of 5 doses. The results suggest that GSH and Cys are potent decorporation agents for (60)Co in the rat model, although the efficacy of treatment depends largely on the systemic availability of the chelator. The intravenous route of administration of GSH or Cys was most effective in reducing tissue (60)Co levels and in increasing excretion of radioactivity compared to control animals. Liposomal encapsulation was found to markedly enhance the oral bioavailability of GSH compared to non-formulated GSH. The oral administration of liposomal GSH reduced (60)Co levels in nearly all tissues by 12-43% compared to that observed for non-formulated GSH. Efficacy of oral Cys was only slightly reduced in comparison with intravenous Cys. Further studies to optimize the dosing regimen in order to maximize decorporation efficiency are warranted. PMID:19959951

  11. Aminothiol Receptors for Decorporation of Intravenously Administered 60Co in the Rat

    PubMed Central

    Levitskaia, Tatiana G.; Morris, James E.; Creim, Jeffrey A.; Woodstock, Angela D.; Luders, Teresa; Curry, Terry L.; Thrall, Karla D.

    2009-01-01

    This report provides a comparison of the oral decorporation efficacy of L-glutathione (GSH), L-cysteine (Cys), and a liposomal GSH formulation (ReadiSorb) toward systemic cobalt-60 (60Co) to that observed following intravenous administration of GSH and Cys in F344 rats. Aminoacid L-histidine (His) containing no thiol functionality was tested intravenously to compare in vivo efficacy of the aminothiol (GSH, Cys) chelators with that of aminoimidazole (His) chelator. In these studies, 60Co was administered to animals by intravenous injection, followed by intravenous or oral gavage doses of a chelator repeated at 24 hour intervals for a total of 5 doses. The results suggest that GSH and Cys are potent decorporation agents for 60Co in the rat model, although the efficacy of treatment depends largely on systemic availability of the chelator. The intravenous route of administration of GSH or Cys was most effective in reducing tissue 60Co levels and in increasing excretion of radioactivity compared to control animals. Liposomal encapsulation was found to markedly enhance the oral bioavailability of GSH compared to non-formulated GSH. The oral administration of liposomal GSH reduced 60Co levels in nearly all tissues by 12-43% compared to that observed for non-formulated GSH. Efficacy of oral Cys was only slightly reduced in comparison with intravenous Cys. Further studies to optimize the dosing regimen in order to maximize decorporation efficiency are warranted. PMID:19959951

  12. Tissue distribution, metabolism and excretion of 3, 3′-dichloro-4′-sulfooxy-biphenyl in the rat

    PubMed Central

    Grimm, Fabian A.; He, Xianran; Teesch, Lynn M.; Lehmler, Hans-Joachim; Robertson, Larry W.; Duffel, Michael W.

    2015-01-01

    Polychlorinated biphenyls (PCBs) with lower numbers of chlorine atoms exhibit a greater susceptibility to metabolism than their higher-chlorinated counterparts. Following initial hydroxylation of these lower chlorinated PCBs, metabolic sulfation to form PCB sulfates is increasingly recognized as an important component of their toxicology. Since procedures for the quantitative analysis of PCB sulfates in tissue samples have not been previously available, we have now developed an efficient, LC-ESI-MS/MS based, protocol for the quantitative analysis of 4-PCB 11 sulfate in biological samples. This procedure was used to determine the distribution of 4-PCB 11 sulfate in liver, kidney, lung, and brain, as well as its excretion profile, following its intravenous administration to male Sprague-Dawley rats. Following initial uptake of 4-PCB 11 sulfate, its concentration in these tissues and serum declined within the first hour following injection. Although biliary secretion was detected, analysis of 24 hour collections of urine and feces revealed recovery of less than 4% of the administered 4-PCB 11 sulfate. High-resolution LC-MS analysis of bile, urine, and feces showed metabolic products derived from 4-PCB 11 sulfate. Thus, 4-PCB 11 sulfate at this dose was not directly excreted in the urine, but was, instead, re-distributed to tissues and/or subjected to further metabolism. PMID:26046945

  13. Decorporation of systemically distributed americium by a novel orally administered diethylenetriaminepentaacetic acid (DTPA) formulation in beagle dogs.

    PubMed

    Wilson, James P; Cobb, Ronald R; Dungan, Nathanael W; Matthews, Laura L; Eppler, Bärbel; Aiello, Kenneth V; Curtis, Shiro; Boger, Teannetta; Guilmette, Raymond A; Weber, Waylon; Doyle-Eisele, Melanie; Talton, James D

    2015-03-01

    Novel decorporation agents are being developed to protect against radiological accidents and terrorists attacks. Radioactive americium is a significant component of nuclear fallout. Removal of large radioactive materials, such as 241Am, from exposed persons is a subject of significant interest due to the hazards they pose. The objective of this study was to evaluate the dose-related efficacy of daily doses of NanoDTPA™ Capsules for decorporating Am administered intravenously as a soluble citrate complex to male and female beagle dogs. In addition, the efficacy of the NanoDTPA™ Capsules for decorporating 241Am was directly compared to intravenously administered saline and DTPA. Animals received a single IV administration of 241Am(III)-citrate on Day 0. One day after radionuclide administration, one of four different doses of NanoDTPA™ Capsules [1, 2, or 6 capsules d(-1) (30 mg, 60 mg, or 180 mg DTPA) or 2 capsules BID], IV Zn-DTPA (5 mg kg(-1) pentetate zinc trisodium) as a positive control, or IV saline as a placebo were administered. NanoDTPA™ Capsules, IV Zn-DTPA, or IV saline was administered on study days 1-14. Animals were euthanized on day 21. A full necropsy was conducted, and liver, spleen, kidneys, lungs and trachea, tracheobronchial lymph nodes (TBLN), muscle samples (right and left quadriceps), gastrointestinal (GI) tract (stomach plus esophagus, upper and lower intestine), gonads, two femurs, lumbar vertebrae (L1-L4), and all other soft tissue remains were collected. Urinary and fecal excretion profiles were increased approximately 10-fold compared to those for untreated animals. Tissue contents were decreased compared to untreated controls. In particular, liver content was decreased by approximately eightfold compared to untreated animals. The results from this study further demonstrate that oral NanoDTPA™ Capsules are equally efficient compared to IV Zn-DTPA in decorporation of actinides. PMID:25627942

  14. Biliary excretion of foreign compounds. Benzene and its derivatives in the rat

    PubMed Central

    Abou-El-Makarem, M. M.; Millburn, P.; Smith, R. L.; Williams, R. T.

    1967-01-01

    1. The extent of the excretion in the bile of the rat of benzene and 21 of its simple derivatives was studied. 2. Some 16 compounds of molecular weight less than 200, and including neutral molecules (benzene and toluene), aromatic acids, aromatic amines and phenols, were injected in solution intraperitoneally into biliary-cannulated rats. Metabolites in the bile were identified and estimated. The extent of biliary excretion of these compounds was low, i.e. 0–10% of the dose in 24hr., and most appeared in the bile mainly as conjugates. 3. The biliary excretion of six conjugates of molecular weight less than 300, including three glycine conjugates, one sulphate conjugate, one glucuronic acid conjugate and two acetyl derivatives, was low (less than 3% of the dose). 4. It is concluded that simple benzene derivatives of molecular weight less than about 300 are poorly excreted in rat bile. PMID:16742555

  15. Effects of chelating agents on oral uptake and renal deposition and excretion of cadmium.

    PubMed Central

    Engström, B

    1984-01-01

    The gastrointestinal absorption, transport, tissue deposition and excretion of cadmium was studied in adult male mice given a single oral LD50 dose of 109Cd-labeled CdCl2 alone or in combination with nitrilotriacetic acid (NTA), sodium tripolyphosphate (STPP) or ethylenediaminetetraacetic acid (EDTA). Blood, intestinal mucosa, liver and kidneys were analyzed for 109Cd at different times after exposure and the influence of the chelating agents on Cd binding to metallothionein and other tissue ligands was also studied. Acute toxicity was noted. Complex formation between Cd and EDTA was studied in solutions containing Cd:EDTA at 1:04 and 1:4 molar ratios. Adult male mice were exposed orally or by direct infusion into the stomach to either of the two solutions (containing an LD50 dose of Cd). Body retention and tissue deposition of Cd was recorded after 4 (direct infusion) or 21 days (oral exposure), and the mortality in different exposure groups observed. Adult male were also exposed to a low oral dose of 109Cd-labeled cadmium (0.5 mg/kg), followed by 18 months continuous administration of NTA, (500 ppm) STPP (500 ppm) or EDTA (50 ppm) in the drinking water or the chelating agent in combination with Cd (50 ppm), Cd alone (50 ppm) or deionized water. Whole-body retention of 109Cd, tissue deposition of 109Cd and total Cd and development of proteinuria were observed. When cadmium was given with an excess of EDTA, all Cd ions were bound in a 1:1 Cd-EDTA complex. Decreased acute toxicity was observed which was related to increased body elimination of cadmium. The Cd passes though the body still bound to EDTA and is excreted via the kidneys in this form. Similar results were found in mice exposed to Cd + NTA, while gavage of CD + STPP led to an initially decreased systemic uptake of Cd and thereafter to a prolongation of the biological half-time and thus a comparatively higher body retention of the metal. Cd may form a 2:1 complex with EDTA in the presence of excess cadmium

  16. Urinary excretion of diazepam metabolites in healthy volunteers and drug users.

    PubMed

    Smith-Kielland, A; Skuterud, B; Olsen, K M; Mørland, J

    2001-05-01

    Urinary excretion profiles of diazepam metabolites were investigated. The subjects were healthy volunteers receiving one single 10-mg dose of diazepam or drug abusers starting a prison sentence. Urinary excretion of metabolites was analysed by immunological screening, liquid chromatography and gas chromatography-mass spectrometry. Relating the metabolite concentration to creatinine concentration in the specimens decreased sample-to-sample variations. In some cases such correction could protect a subject from erroneous accusations of a new intake. PMID:11386610

  17. Excretion of copper complexed with thiomolybdate into the bile and blood in LEC rats.

    PubMed

    Komatsu, Y; Sadakata, I; Ogra, Y; Suzuki, K T

    2000-02-01

    Copper (Cu) accumulating in a form bound to metallothionein (MT) in the liver of Long-Evans rats with a cinnamon-like coat color (LEC rats), an animal model of Wilson disease, was removed with ammonium tetrathiomolybdate (TTM), and the fate of the Cu complexed with TTM and mobilized from the liver was determined. TTM was injected intravenously as a single dose of 2, 10 or 50 mg TTM/kg body weight into LEC and Wistar (normal Cu metabolism) rats, and then the concentrations of Cu and molybdenum (Mo) in the bile and plasma were monitored with time after the injection. In Wistar rats, most of the Mo was excreted into the urine, only a small quantity being excreted into the bile, while Cu excreted into the urine decreased. However, in LEC rats, Cu and Mo were excreted into the bile and blood, and the bile is recognized for the first time as the major route of excretion. The Cu excreted into both the bile and plasma was accompanied by an equimolar amount of Mo. The relative ratio of the amounts of Cu excreted into the bile and plasma was 40/60 for the low and high dose groups, and 70/30 for the medium dose group. The systemic dispositions of the Cu mobilized from the liver and the Mo complexed with the Cu were also determined for the kidneys, spleen and brain together with their urinal excretion. Although Mo in the three organs and Cu in the kidneys and spleen were increased or showed a tendency to increase, Cu in the brain was not increased at all doses of TTM. PMID:10728780

  18. Centrally administered naloxone blocks reflex natriuresis after acute unilateral nephrectomy.

    PubMed

    Lin, S Y; Humphreys, M H

    1985-09-01

    Acute unilateral nephrectomy (AUN) leads to a natriuresis and kaliuresis by the remaining kidney through reflex mechanisms involving opiate receptors. To determine whether the opiate receptors mediating these responses are located in the central nervous system, we carried out AUN in anesthetized rats undergoing continuous ventriculocisternal perfusion (VCP) with artificial cerebrospinal fluid (CSF). AUN caused large increases in both Na (UNaV) and K (UKV) excretion without changes in glomerular filtration rate or arterial blood pressure. When the opiate receptor antagonist naloxone was added to the perfusate to achieve a perfusion rate of 32 micrograms X kg-1 X h-1, AUN failed to increase either UNaV or UKV by the remaining kidney. This dose of naloxone, however, was without effect when infused intravenously. Addition of thyrotropin-releasing hormone (TRH) to the artificial CSF to achieve a VCP rate of 50 micrograms X kg-1 X h-1 also blocked the expected increase in UNaV and UKV by the remaining kidney after AUN. Infusion of TRH intravenously at the same rate did not interfere with the postnephrectomy natriuresis or kaliuresis. Higher intravenous infusion rates of TRH (1 and 2 mg X kg-1h-1) prevented the postnephrectomy natriuresis without affecting the kaliuresis. These results indicate that the effect of naloxone to block the reflex natriuresis and kaliuresis after AUN resides largely in the central nervous system. The blockade by naloxone of the postnephrectomy natriuresis is duplicated by centrally administered TRH, providing another example of the interaction of this hormone with the endogenous opioid system. Large intravenous infusions of TRH also block the postnephrectomy natriuresis but not the kaliuresis. PMID:3929623

  19. Radiation dose estimates for C-11 iomazenil, a benzodiazepine receptor radioligand

    SciTech Connect

    Sparks, R.B.; Dey, H.M.; Siebyl, I.B.

    1994-05-01

    SPECT imaging of the brain with I-123 iomazenil has shown avid uptake of the radioligand in a distribution consistent with benzodiazepine receptor binding. It was desirable to radiolabel this compound with a positron emitting radionuclide so that quantitation of the receptor density could be assessed with PET imaging. Radiation dose estimates for C-11 iomazenil were calculated prior to obtaining Institutional Review Board approval of this procedure. A previously published multicompartmental model was used as the biological model for estimating residence times associated with the C-11 labeled iomazenil. According to this model, 85-90% is excreted in the urine and 10-15% in the feces. A dynamic, voiding urinary bladder model was utilized for activity excreted renally and the ICRP 30 gastrointestinal tract kinetic model was used for activity excreted via the hepatobiliary system. Absorbed doses from C-11 (I-123) iomazenil to the urinary bladder were calculated to be 0.099 mGy/MBq (0.19 mGy/MBq) for a 4.8 hour bladder voiding interval. Shortening the bladder voiding interval to 2.0 hours had little effect on the bladder wall dose (0.095 mGy/MBq). However, a 30-minute void interval was estimated to lower the bladder wall dose substantially (0.045 mGy/MBq). Absorbed dose to the kidney was higher for C-11 iomazenil (0.054 vs 0.031 mGy/MBq) than for I-123 iomazenil due to rapid, early renal excretion of this very short-lived positron emitter. Doses to the gastrointestinal tract were estimated to be 4- to 20-fold lower for C-11 iomazenil compared to I-123 iomazenil. Overall, labeling iomazenil with C-11 rather than I-123 greatly reduces the radiation dose, per unit administered, to all organs except the kidneys.

  20. Disposition of decabromobiphenyl ether in rats dosed intravenously or by feeding

    SciTech Connect

    El Dareer, S.M.; Kalin, J.R.; Tillery, K.F.; Hill, D.L.

    1987-01-01

    The disposition of /sup 14/C-labeled decabromobiphenyl ether (DBBE) in male Fischer rats dosed by feeding (0.025-5.0% of the diet) or intravenously (1 mg/kg) was determined. For rats dosed by feeding, intestinal absorption of DBBE was evident in that the intact compound was present in extracts of liver. For these rats, the size of the liver increased with increasing concentration of DBBE in the diet. Liver contained a maximum of 0.449% of the administered radioactivity at 24 h after feeding rats a diet containing 0.0277% (/sup 14/C)DBBE; no other organ or tissue contained more than 0.26%. The total amount of radioactivity found in tissues was less than 1% of the dose. Of the radioactivity recovered in the feeding experiments, more than 99% was in the feces and gut contents at 72 h; a maximum of 0.012% of the dose was in the urine. In the feces of rats fed (/sup 14/C)DBBE, there were three metabolites, which together comprised 1.5-27.9% of the radioactivity. Since absorption was minimal, most of the metabolism of (/sup 14/C)DBBE apparently took place in the gastrointestinal tract. The metabolites increased in percent of total radioactivity with the content of DBBE in the diet, an indication that enzyme induction in intestinal bacteria may have occurred at the higher doses. More extensive metabolism of (/sup 14/C)DBBE occurred after intravenous administration; only 37% of the radioactivity in the feces was unchanged DBBE. At 72 h after dosing, fecal excretion accounted for 70% of the dose; only 0.129% appeared in the urine. Muscle retained 12.9% and skin 7.25% of the radioactivity administered. In 4 h, rats with biliary cannulas excreted in the bile 7.17% of the intravenously administered radioactivity; less than 1% was excreted as intact DBBE. Biliary excretion was apparently the major route for elimination of the intravenously administered compound.

  1. Polychlorinated Biphenyl Congeners that Increase the Glucuronidation and Biliary Excretion of Thyroxine Are Distinct from the Congeners that Enhance the Serum Disappearance of Thyroxine

    PubMed Central

    Martin, L. A.; Wilson, D. T.; Reuhl, K. R.; Gallo, M. A.

    2012-01-01

    Polychlorinated biphenyl (PCB) congeners differentially reduce serum thyroxine (T4) in rats, but little is known about their ability to affect biliary excretion of T4. Thus, male Sprague-Dawley rats were orally administered Aroclor-1254, Aroclor-1242 (32 mg/kg per day), PCB-95, PCB-99, PCB-118 (16 mg/kg per day), PCB-126 (40 μg/kg per day), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (3.9 μg/kg per day), or corn oil for 7 days. Twenty-four hours after the last dose, [125I]T4 was administered intravenously, and blood, bile, and urine samples were collected for quantifying [125I]T4 and in bile [125I]T4 metabolites. Serum T4 concentrations were reduced by all treatments, but dramatic reductions occurred in response to Aroclor-1254, PCB-99 [phenobarbital (PB)-type congener], and PCB-118 (mixed-type congener). None of the treatments increased urinary excretion of [125I]T4. Aroclor-1254, PCB-118, TCDD, and PCB-126 (TCDD-type congener) increased biliary excretion of T4-glucuronide by 850, 756, 710, and 573%, respectively, corresponding to marked induction of hepatic UDP-glucuronosyltransferase (UGT) activity toward T4. PCB-95 and PCB-99 did not induce UGT activity; therefore, the increased biliary excretion of T4-glucuronide was related to the affinity of congeners for the aryl hydrocarbon receptor. The disappearance of [125I]T4 from serum was rapid (within 15-min) and was increased by Aroclor-1254, PCB-99 and PCB-118. Thus, reductions in serum T4 in response to PCBs did not always correspond with UGT activity toward T4 or with increased biliary excretion of T4-glucuronide. The rapid disappearance of [125I]T4 from the serum of rats treated with PB-like PCBs suggests that increased tissue uptake of T4 is an additional mechanism by which PCBs may reduce serum T4. PMID:22187485

  2. Influence of DTPA Treatment on Internal Dose Estimates.

    PubMed

    Davesne, Estelle; Blanchardon, Eric; Peleau, Bernadette; Correze, Philippe; Bohand, Sandra; Franck, Didier

    2016-06-01

    In case of internal contamination with plutonium materials, a treatment with diethylene triamine pentaacetic acid (DTPA) can be administered in order to reduce plutonium body burden and consequently avoid some radiation dose. DTPA intravenous injections or inhalation can start almost immediately after intake, in parallel with urinary and fecal bioassay sampling for dosimetric follow-up. However, urine and feces excretion will be significantly enhanced by the DTPA treatment. As internal dose is calculated from bioassay results, the DTPA effect on excretion has to be taken into account. A common method to correct bioassay data is to divide it by a factor representing the excretion enhancement under DTPA treatment by intravenous injection. Its value may be based on a nominal reference or observed after a break in the treatment. The aim of this study was to estimate the influence of this factor on internal dose by comparing the dose estimated using default or upper and lower values of the enhancement factor for 11 contamination cases. The observed upper and lower values of the enhancement factor were 18.7 and 63.0 for plutonium and 24.9 and 28.8 for americium. For americium, a default factor of 25 is proposed. This work demonstrates that the use of a default DTPA enhancement factor allows the determination of the magnitude of the contamination because dose estimated could vary by a factor of 2 depending on the value of the individual DTPA enhancement factor. In case of significant intake, an individual enhancement factor should be determined to obtain a more reliable dose assessment. PMID:27115221

  3. Disposition, metabolism, and excretion of [14C]doripenem after a single 500-milligram intravenous infusion in healthy men.

    PubMed

    Cirillo, Iolanda; Mannens, Geert; Janssen, Cor; Vermeir, Marc; Cuyckens, Filip; Desai-Krieger, Daksha; Vaccaro, Nicole; Kao, L Mark; Devineni, Damayanthi; Redman, Rebecca; Turner, Kenneth

    2008-10-01

    In this open-label, single-center study, eight healthy men each received a single 500-mg dose of [(14)C]doripenem, containing 50 microCi of [(14)C]doripenem, administered as a 1-h intravenous infusion. The concentrations of unchanged doripenem and its primary metabolite (doripenem-M-1) resulting from beta-lactam ring opening were measured in plasma and urine by a validated liquid chromatography method coupled to a tandem mass spectrometry assay. Total radioactivity was measured in blood, plasma, urine, and feces by liquid scintillation counting. Further metabolite profiling was conducted on urine samples using liquid chromatography coupled to radiochemical detection and high-resolution mass spectrometry. Unchanged doripenem and doripenem-M-1 accounted for means of 80.7% and 12.7% of the area under the plasma total-radioactivity-versus-time curve (area under the concentration-time curve extrapolated to infinity) and exhibited elimination half-lives of 1.1 and 2.5 h, respectively. Total clearance of doripenem was 16 liters/h, and renal clearance was 12.5 liters/h. At 7 days after the single dose, 95.3% of total doripenem-related radioactivity was recovered in urine and 0.72% in feces. A total mean of 97.2% of the administered dose was excreted in the urine as unchanged doripenem (78.7% +/- 5.7%) and doripenem-M-1 (18.5% +/- 2.6%). Most of the urinary recovery occurred within 4 h of dosing. Three additional minor metabolites were identified in urine: the glycine and taurine conjugates of doripenem-M-1 and oxidized doripenem-M-1. These results show that doripenem is predominantly eliminated in urine as unchanged drug, with only a fraction metabolized to doripenem-M-1 and other minor metabolites. PMID:18644951

  4. Salivary excretion of rabies virus by healthy vampire bats.

    PubMed

    Aguilar-Setien, A; Loza-Rubio, E; Salas-Rojas, M; Brisseau, N; Cliquet, F; Pastoret, P P; Rojas-Dotor, S; Tesoro, E; Kretschmer, R

    2005-06-01

    Salivary excretion of rabies virus was evaluated in 14 adult vampire bats (Desmodus rotundus) intramuscularly injected with a large dose (10(6) MICLD50) of vampire rabies virus variant CASS88. Saliva samples were obtained from surviving bats every other day for 30 days, then weekly for 2 months, and finally 1 and 2 years later. Rabies virus was isolated in murine neuroblastoma cells and in randomly selected cases by PCR. Rabies virus was not detected in the saliva of any of the 11 animals that succumbed (somewhat early) to rabies challenge, nor in the control bats. In contrast, virus was detected early, and only once (days 6, 6 and 21) in each of the three animals that survived rabies challenge and remained healthy for at least 2 years after challenge. At that time even vigorous dexamethasone and cyclosporine administration failed to provoke further viral excretion. PMID:15966107

  5. Salivary excretion of rabies virus by healthy vampire bats.

    PubMed Central

    Aguilar-Setien, A.; Loza-Rubio, E.; Salas-Rojas, M.; Brisseau, N.; Cliquet, F.; Pastoret, P. P.; Rojas-Dotor, S.; Tesoro, E.; Kretschmer, R.

    2005-01-01

    Salivary excretion of rabies virus was evaluated in 14 adult vampire bats (Desmodus rotundus) intramuscularly injected with a large dose (10(6) MICLD50) of vampire rabies virus variant CASS88. Saliva samples were obtained from surviving bats every other day for 30 days, then weekly for 2 months, and finally 1 and 2 years later. Rabies virus was isolated in murine neuroblastoma cells and in randomly selected cases by PCR. Rabies virus was not detected in the saliva of any of the 11 animals that succumbed (somewhat early) to rabies challenge, nor in the control bats. In contrast, virus was detected early, and only once (days 6, 6 and 21) in each of the three animals that survived rabies challenge and remained healthy for at least 2 years after challenge. At that time even vigorous dexamethasone and cyclosporine administration failed to provoke further viral excretion. PMID:15966107

  6. Metabolism of T-2 toxin in rats and rabbits: effects of dose, route, and time

    SciTech Connect

    Pfeiffer, R.L.

    1986-01-01

    Male, Sprague-Dawley rats and male New Zealand White rabbits were administered tritium-labeled T-2 toxin at 0.15 mg/kg and 0.60 mg/kg of body weight by i.v., oral and dermal routes of administration. The excretion of total radioactivity was determined for six days and the metabolic profiles were determined using HPLC for days 1, 2 and 3. The excretion of radioactivity in the excreta of both species was rapid and nearly complete after 6 days (>95%) in i.v. and orally dosed animals, but only 70 to 80 percent of the administered radioactivity was excreted in dermally dosed rats and rabbits. The major metabolites in the excreta of rats and rabbits were 3'OH HT-2, HT-2, T-2 tetraol, deepoxy T-2 tetraol and several unknowns. In urine and fecal extracts from rats, these metabolites accounted for 59 and 25% of the extracted radioactivity, respectively. An unknown metabolite, tentatively identified as deepoxy 3'OH HT-2 accounted for another 47% of the extracted radioactivity in fecal extracts from rats. In urine and fecal extracts from rabbits, these major metabolites accounted for 71 and 60% of the extracted radioactivity, respectively. An unknown metabolite, tentatively identified as deepoxy 3'OH HT-2 accounted for an additional 26% of the extracted radioactivity in fecal extracts.

  7. The radiation dosimetry of intrathecally administered radionuclides

    SciTech Connect

    Stabin, M.G.; Evans, J.F.

    1999-01-01

    The radiation dose to the spine, spinal cord, marrow, and other organs of the body from intrathecal administration of several radiopharmaceuticals was studied. Anatomic models were developed for the spine, spinal cerebrospinal fluid (CSF), spinal cord, spinal skeleton, cranial skeleton, and cranial CSF. A kinetic model for the transport of CSF was used to determine residence times in the CSF; material leaving the CSF was thereafter assumed to enter the bloodstream and follow the kinetics of the radiopharmaceutical as if intravenously administered. The radiation transport codes MCNP and ALGAMP were used to model the electron and photon transport and energy deposition. The dosimetry of Tc-99m DTPA and HSA, In-111 DTPA, I-131 HSA, and Yb-169 DTPA was studied. Radiation dose profiles for the spinal cord and marrow in the spine were developed and average doses to all other organs were estimated, including dose distributions within the bone and marrow.

  8. Estimation of biliary excretion of foreign compounds using properties of molecular structure.

    PubMed

    Sharifi, Mohsen; Ghafourian, Taravat

    2014-01-01

    Biliary excretion is one of the main elimination pathways for drugs and/or their metabolites. Therefore, an insight into the structural profile of cholephilic compounds through accurate modelling of the biliary excretion is important for the estimation of clinical pharmacokinetics in early stages of drug discovery. The aim of this study was to develop quantitative structure-activity relationships as computational tools for the estimation of biliary excretion and identification of the molecular properties controlling this process. The study used percentage of dose excreted intact into bile measured in vivo in rat for a diverse dataset of 217 compounds. Statistical techniques were multiple linear regression analysis, regression trees, random forest and boosted trees. A simple regression tree model generated using the CART algorithm was the most accurate in the estimation of the percentage of bile excretion of compounds, and this outperformed the more sophisticated boosted trees and random forest techniques. Analysis of the outliers indicated that the models perform best when lipophilicity is not too extreme (log P < 5.35) and for compounds with molecular weight above 280 Da. Molecular descriptors selected by all these models including the top ten incorporated in boosted trees and random forest indicated a higher biliary excretion for relatively hydrophilic compounds especially if they are anionic or cationic, and have a large molecular size. A statistically validated molecular weight threshold for potentially significant biliary excretion was above 348 Da. PMID:24202722

  9. Absolute bioavailability and disposition of lanthanum in healthy human subjects administered lanthanum carbonate.

    PubMed

    Pennick, Michael; Dennis, Kerry; Damment, Stephen J P

    2006-07-01

    Lanthanum carbonate [La2(CO3)3] is a noncalcium, non-aluminum phosphate binder indicated for hyperphosphatemia treatment in end-stage renal disease. A randomized, open-label, parallel-group, phase I study was conducted to determine absolute bioavailability and investigate excretory routes for systemic lanthanum in healthy subjects. Twenty-four male subjects were randomized to a single lanthanum chloride (LaCl3) intravenous infusion (120 microg elemental lanthanum over a 4-hour period), a single 1-g oral dose [chewable La2(CO3)3 tablets; 4 x 250 mg elemental lanthanum], or no treatment (control). Serial blood, urine, and fecal samples were collected for 7 days postdosing. The absolute bioavailability of lanthanum [administered as La2(CO3)3] was extremely low (0.00127% +/- 0.00080%), with individual values in the range of 0.00015% to 0.00224%. Renal clearance was negligible following oral administration (1.36 +/- 1.43 mL/min). Intravenous administration confirmed low renal clearance (0.95 +/- 0.60 mL/min), just 1.7% of total plasma clearance. Fecal lanthanum excretion was not quantifiable after intravenous administration owing to high and variable background fecal lanthanum and constraints on the size of the intravenous dose. These findings demonstrate that lanthanum absorption from the intestinal tract into the systemic circulation is extremely low and that absorbed drug is cleared predominantly by nonrenal mechanisms. PMID:16809799

  10. Absorption, distribution, metabolism, excretion, and kinetics of 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoic acid ammonium salt following a single dose in rat, mouse, and cynomolgus monkey.

    PubMed

    Gannon, Shawn A; Fasano, William J; Mawn, Michael P; Nabb, Diane L; Buck, Robert C; Buxton, L William; Jepson, Gary W; Frame, Steven R

    2016-01-18

    Ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate has been developed as a processing aid used in the manufacture of fluoropolymers. The absorption, distribution, elimination, and distribution (ADME) and kinetic behavior of this substance has been evaluated in rats, mice, and cynomolgus monkeys by oral and intravenous routes of exposure and studied in both plasma and urine. The test substance is rapidly and completely absorbed in both rats and mice and both in vivo and in vitro experiments indicate that it is not metabolized. The test substance is rapidly eliminated exclusively in the urine in both rats and mice, with rats eliminating it more quickly than mice (approximately 5h elimination half-life in rats, 20 h half-life in mice). Pharmacokinetic analysis in monkeys, rats, and mice indicate rapid, biphasic elimination characterized by a very fast alpha phase and a slower beta phase. The beta phase does not contribute to potential accumulation after multiple dosing in rats or monkeys. Comparative pharmacokinetics in rats, mice, and monkeys indicates that the rat is more similar to the monkey and is therefore a more appropriate rodent model for pharmacokinetics in primates. PMID:26743852

  11. Assessment of urinary excretion of antimalarial drugs in large-scale chemotherapeutic eradication projects.

    PubMed

    BRUCE-CHWATT, L J

    1959-01-01

    Assessment of the urinary excretion of an antimalarial drug is a useful means of checking the amount of drug administered and the regularity of intake. The author describes the various methods available for the qualitative and quantitative estimation of antimalarial drugs in urine and discusses their relative merits, with special reference to their suitability for use in the field. He points out the difficulties involved in estimating the urinary excretion of antimalarials in large-scale chemotherapeutic eradication projects and stress the importance of simplifying testing techniques as far as possible. PMID:13805135

  12. [Absorption, excretion and clinical trials of cefroxadine in the field of pediatrics (author's transl)].

    PubMed

    Motohiro, T; Sakata, Y; Fujimoto, T; Nishiyama, T; Nakajima, T; Ishimoto, K; Tominaga, K; Yamashita, F; Takajo, N; Araki, H; Shiozuki, Y; Takenaka, S; Kamezaki, K; Yoshinaga, Y; Kawano, N; Yamamoto, M; Komatsu, R; Ohta, M; Etoh, Y; Moroi, T; Iriki, T; Chou, H; Okada, S; Kinoshita, M; Imuta, F; Koga, T

    1981-12-01

    A study was made with the newly developed cefroxadine (CXD) dry syrup by measuring the serum level, urine excretion and recovery rate in 10 children who were orally administered 5, 10 and 20 mg/kg at 1 hour after meals and the following results were gained. Also, its clinical efficacies and side effects were investigated in the following cases who were treated with a mean dose of 33 mg/day divided into 3 to 4 portions for a period of 9 days on the average; viz. a total of 151 cases consisting of 9 cases of pharyngitis, 39 of tonsillitis, 11 of streptococcal infection, i.e. scarlet fever, 7 of bronchitis, 6 of pneumonia, 1 of otitis media, 6 of purulent lymphadenitis, 1 of purulent parotitis, 1 of subcutaneous abscess and 3 of impetigo. 1. The serum level tends to reach its maximum level within 1 hour after administration. The mean concentrations of 5, 10 and 20 mg/kg dose in the foregoing time were 6.35, 9.12 and 21.62 mcg/ml respectively and dose response was observed. CXD showed higher concentration than CEX, CED and CFT. The mean half-life periods of the 3 dose were 72, 84 and 66 minutes respectively and variations were observed, but the drugs maintains a satisfactory serum level. 2. The time which showed highest urine excretion was mainly in the 0 to 2 hours bracket and the average concentrations of 5 , 10 and 20 mg/kg dose in the foregoing time were 381.2, 771.7 and 1,577.7 mcg/ml respectively. The dose response was more evident than in the serum concentrations. The average recovery rates within 6 hours were 93.6, 88.3 and 94.3% respectively and they were similar to those of CEX, CED and CFT. 3. The clinical effects were evaluated were in 148 cases out of the total of 151 and 136 cases, or 91.9% showed good or excellent efficacy response. 4. The daily dose groups of less than 30 mg/kg and 31 to 40 mg/kg formed the majority and there was no difference in the comparison of the clinical effectiveness in these 2 groups. Administration of a daily dose of 20 to 40

  13. Dietary isoflavone absorption, excretion, and metabolism in captive cheetahs (Acinonyx jubatus).

    PubMed

    Whitehouse-Tedd, Katherine M; Cave, Nicholas J; Ugarte, Claudia E; Waldron, Lucy A; Prasain, Jeevan K; Arabshahi, Alireza; Barnes, Stephen; Thomas, David G

    2011-12-01

    Dietary isoflavones, capable of influencing reproductive parameters in domestic cats (Felis catus), have been detected in commercial diets fed to captive cheetahs (Acinonyx jubatus). However, the absorptive and metabolic capacity of cheetahs towards isoflavones has not yet been studied. Experiments were designed to describe the plasma concentration-time curve, metabolite profile, and urinary and fecal excretion of genistein and daidzein in cheetahs following consumption of isoflavones. Four adult cheetahs were administered a single oral bolus of genistein and daidzein, and five juvenile cheetahs consuming a milk replacer formula found to contain isoflavones were also included. Urine was collected from all animals, and blood and feces were also collected from adult cheetahs following isoflavone exposure. Samples were analyzed for isoflavone metabolite concentration by liquid chromatography-electrospray ionization-multiple reaction ion monitoring mass spectrometry and high-performance liquid chromatography. Sulfate conjugates were the primary metabolites detected of both genistein and daidzein (60-80% of total isoflavones present) in the plasma and urine of cheetahs. A smaller proportion of daidzein was detected as conjugates in the urine of juvenile cheetahs, compared to adult cheetahs. Other metabolites included unconjugated genistein and daidzein, O-desmethylangolensin, and dihydrodaidzein, but not equol. Only 33% of the ingested genistein dose, and 9% of daidzein, was detected in plasma from adult cheetahs. However, of the ingested dose, 67% of genistein and 45% of daidzein were detected in the feces of adults. This study revealed that cheetahs appear efficient in their conjugation of absorbed dietary isoflavones and only a small fraction of ingested dose is absorbed. However, the capacity of the cheetah to conjugate genistein and daidzein with sulfate moieties appears lower than reported in the domestic cat. This may confer greater opportunity for biologic

  14. Vasopressin regulates renal calcium excretion in humans

    PubMed Central

    Hanouna, Guillaume; Haymann, Jean-Philippe; Baud, Laurent; Letavernier, Emmanuel

    2015-01-01

    Antidiuretic hormone or arginine vasopressin (AVP) increases water reabsorption in the collecting ducts of the kidney. Three decades ago, experimental models have shown that AVP may increase calcium reabsorption in rat kidney. The objective of this study was to assess whether AVP modulates renal calcium excretion in humans. We analyzed calcium, potassium, and sodium fractional excretion in eight patients affected by insipidus diabetes (nephrogenic or central) under acute vasopressin receptor agonist action and in 10 patients undergoing oral water load test affected or not by inappropriate antidiuretic hormone secretion (SIADH). Synthetic V2 receptor agonist (dDAVP) reduced significantly calcium fractional excretion from 1.71% to 0.58% (P < 0.05) in patients with central diabetes insipidus. In patients with nephrogenic diabetes insipidus (resistant to AVP), calcium fractional excretion did not change significantly after injection (0.48–0.68%, P = NS). In normal subjects undergoing oral water load test, calcium fractional excretion increased significantly from 1.02% to 2.54% (P < 0.05). Patients affected by SIADH had a high calcium fractional excretion at baseline that remained stable during test from 3.30% to 3.33% (P = NS), possibly resulting from a reduced calcium absorption in renal proximal tubule. In both groups, there was a significant correlation between urine output and calcium renal excretion. In humans, dDAVP decreases calcium fractional excretion in the short term. Conversely, water intake, which lowers AVP concentration, increases calcium fractional excretion. The correlation between urine output and calcium excretion suggests that AVP-related antidiuresis increases calcium reabsorption in collecting ducts. PMID:26620256

  15. Pharmacokinetics of biliary excretion of N-nitrosodiphenylamine (NDPA) in animals of different species.

    PubMed

    Atawodi, S E; Maduagwu, E N

    1990-01-01

    Pharmacokinetic investigations into the biliary excretion of N-nitrosodiphenylamine given as an i.p. dose of 50 mg/kg were conducted and results compared in three animal species; rat, guinea pig and rabbit following bile duct cannulation and collection of bile in vitro. The guinea pig excreted NDPA into bile fastest while the rabbit, which excreted it slowest, eliminated it fastest. Both appearance and disappearance of the nitrosamine were comparatively slow in the rat. NDPA elimination half-life values in the animal species were 510, 240 and 95 min respectively, while cumulative excretions amounted to 12, 3 and 0.3 percent. The toxicological implications of these species differences are highlighted. PMID:2384114

  16. Pharmacokinetics, tissue distribution, excretion, and metabolite profiling of PEGylated rFIX (nonacog beta pegol, N9-GP) in rats.

    PubMed

    Sternebring, Ola; Christensen, Jesper Kammersgaard; Bjørnsdottir, Inga

    2016-09-20

    Nonacog beta pegol (N9-GP) is a novel recombinant factor IX conjugated with a 40-kDa branched polyethylene glycol (PEG) to extend plasma half-life (t½) compared with native FIX, developed for the treatment of haemophilia B. This is the first time distribution, metabolism, and excretion data of N9-GP have been presented. ADME studies were performed using single i.v. doses of radiolabelled N9-GP administered to rats, focussing on the biological fate of the 40-kDa PEG. Results indicated that N9-GP-related radioactivity was distributed throughout the body, being most abundant in highly vascularised tissues, and with lowest levels seen in the central nervous system. N9-GP was cleared from plasma within 1week after dosing, while total radioactivity was eliminated more slowly, in a more pronounced biphasic manner. N9-GP seems to be cleared via receptor-mediated uptake (e.g., in the liver) or via the reticuloendothelial system with subsequent proteolysis. PEG is thereafter either cleared alongside the protein or released back into circulation. Furthermore, N9-GP-related radioactivity was excreted in both faeces and urine as 40kDa PEG and degradation products. Some PEG-related radioactivity (not in any particular organ) was present in the carcass 12weeks postdose, consistent with the long terminal elimination t½ of plasma radioactivity. As shown here for N9-GP, and previously for other protein-PEG conjugate products, disposition kinetics of conjugates and individual constituents appears to be compound specific. In addition to the size/structure of the PEG and protein moieties, protein-specific clearance pathways may contribute to the disposition of intact conjugate and PEG moiety. PMID:27378188

  17. The bioavailability of an orally administered medroxyprogesterone acetate suspension.

    PubMed

    Antal, E J; Gillespie, W R; Albert, K S

    1983-05-01

    The relative bioavailability of an orally administered aqueous suspension of medroxyprogesterone acetate (MPA) intended for intramuscular injection (Depo-Provera) was determined in relation to orally administered tablets. Serum levels of MPA were determined by radioimmunoassay following the administration of 400-mg doses to 19 adult male volunteers in a crossover design after an overnight fast. The two treatments were judged bioequivalent based upon a comparison of the resultant MPA serum levels and the derived bioavailability parameters. Hence, the intramuscular suspension administered orally offers an alternative means of achieving optimal serum levels of MPA in patients requiring high dose therapy. PMID:6222996

  18. Radiation dosimetry from breast milk excretion of radioiodine and pertechnetate

    SciTech Connect

    Hedrick, W.R.; Di Simone, R.N.; Keen, R.L.

    1986-10-01

    Measurements were made of the activity in samples of breast milk obtained from a patient with postpartum thyroiditis following administration of (/sup 123/I)sodium iodide and subsequently (99mTc)pertechnetate 24 hr later. Both /sup 123/I and 99mTc were found to be excreted exponentially with an effective half-life of 5.8 hr and 2.8 hr, respectively. Less than 10% of the activity was incorporated into breast-milk protein. After administration of (/sup 123/I)sodium iodide breast feeding should be discontinued for 24-36 hr to reduce the absorbed dose to the child's thyroid.

  19. Urinary porphyrin excretion in hepatitis C infection.

    PubMed

    Vogeser, M; Jacob, K; Zachoval, R

    1999-08-01

    A high prevalence of hepatitis C virus infection in porphyria cutanea tarda in some populations suggests a close link between viral hepatitis and alteration of porphyrin metabolism. Moreover, there is evidence of a role of porphyrinopathies in hepatocarcinogenesis. The aim of our study was to obtain data on the prevalence and patterns of heme metabolism alterations in patients with chronic hepatitis C virus infection. Urinary porphyrin excretion was prospectively studied in 100 consecutive outpatients with chronic hepatitis C infection without signs of photosensitivity, using an ion-pair high-performance liquid chromatography method. Increased total porphyrin excretion was found in 41 patients, with predominant excretion of coproporphyrins (whole study group: mean 146 microg/g creatinine, interquartile range 76-186; normal < 150), in 10 patients excretion exceeded 300 microg/g creatinine. In the majority of all patients studied (75/100) an increased ratio of the relatively hydrophobic coproporphyrin isomer I to isomer III was found. In just one case, urinary porphyrin pattern characteristic for chronic hepatic porphyria was present (uroporphyrin > coproporphyrin, heptacarboxyporphyrin III increased) but the total porphyrin excretion was only slightly elevated in this case. In the whole group, total urinary porphyrin excretion correlated well with serum bilirubin and was inversely correlated with albumin and thrombin time. In conclusion, secondary coproporphyrinuria occurs frequently in heptatitis C infection, whereas in Germany, preclinical porphyria cutanea tarda seems to be rare in these patients. PMID:10536928

  20. Effects of SiC nanoparticles orally administered in a rat model: Biodistribution, toxicity and elemental composition changes in feces and organs

    SciTech Connect

    Lozano, Omar; Laloy, Julie; Alpan, Lütfiye; Mejia, Jorge; Rolin, Stéphanie; Toussaint, Olivier; Dogné, Jean-Michel; and others

    2012-10-15

    Background: Silicon carbide (SiC) presents noteworthy properties as a material such as high hardness, thermal stability, and photoluminescent properties as a nanocrystal. However, there are very few studies in regard to the toxicological potential of SiC NPs. Objectives: To study the toxicity and biodistribution of silicon carbide (SiC) nanoparticles in an in vivo rat model after acute (24 h) and subacute (28 days) oral administrations. The acute doses were 0.5, 5, 50, 300 and 600 mg·kg{sup −1}, while the subacute doses were 0.5 and 50 mg·kg{sup −1}. Results: SiC biodistribution and elemental composition of feces and organs (liver, kidneys, and spleen) have been studied by Particle-Induced X-ray Emission (PIXE). SiC and other elements in feces excretion increased by the end of the subacute assessment. SiC did not accumulate in organs but some elemental composition modifications were observed after the acute assessment. Histopathological sections from organs (stomach, intestines, liver, and kidneys) indicate the absence of damage at all applied doses, in both assessments. A decrease in the concentration of urea in blood was found in the 50 mg·kg{sup −1} group from the subacute assessment. No alterations in the urine parameters (sodium, potassium, osmolarity) were found. Conclusion: This is the first study that assesses the toxicity, biodistribution, and composition changes in feces and organs of SiC nanoparticles in an in vivo rat model. SiC was excreted mostly in feces and low traces were retrieved in urine, indicating that SiC can cross the intestinal barrier. No sign of toxicity was however found after oral administration. -- Highlights: ► SiC nanoparticles were orally administered to rats in acute and subacute doses. ► SiC was found in low traces in urine. It is mostly excreted in feces within 5 days. ► SiC excretion rate, feces and organ elemental composition change with time. ► No morphological alteration were found on GI tract, liver, kidneys

  1. Safety and persistence of the humoral and cellular immune responses induced by 2 doses of an AS03-adjuvanted A(H1N1)pdm09 pandemic influenza vaccine administered to infants, children and adolescents: Two open, uncontrolled studies

    PubMed Central

    Garcia-Sicilia, José; Arístegui, Javier; Omeñaca, Félix; Carmona, Alfonso; Tejedor, Juan C; Merino, José M; García-Corbeira, Pilar; Walravens, Karl; Bambure, Vinod; Moris, Philippe; Caplanusi, Adrian; Gillard, Paul; Dieussaert, Ilse

    2015-01-01

    In children, 2 AS03-adjuvanted A(H1N1)pdm09 vaccine doses given 21 days apart were previously shown to induce a high humoral immune response and to have an acceptable safety profile up to 42 days following the first vaccination. Here, we analyzed the persistence data from 2 open-label studies, which assessed the safety, and humoral and cell-mediated immune responses induced by 2 doses of this vaccine. The first study was a phase II, randomized trial conducted in 104 children aged 6–35 months vaccinated with the A(H1N1)pdm09 vaccine containing 1.9 µg haemagglutinin antigen (HA) and AS03B (5.93 mg tocopherol) and the second study, a phase III, non-randomized trial conducted in 210 children and adolescents aged 3–17 years vaccinated with the A(H1N1)pdm09 vaccine containing 3.75 µg HA and AS03A (11.86 mg tocopherol). Approximately one year after the first dose, all children with available data were seropositive for haemagglutinin inhibition and neutralising antibody titres, but a decline in geometric mean antibody titres was noted. The vaccine induced a cell-mediated immune response in terms of antigen-specific CD4+ T-cells, which persisted up to one year post-vaccination. The vaccine did not raise any safety concern, though these trials were not designed to detect rare events. In conclusion, 2 doses of the AS03-adjuvanted A(H1N1)pdm09 vaccine at 2 different dosages had a clinically acceptable safety profile, and induced high and persistent humoral and cell-mediated immune responses in children aged 6–35 months and 3–17 years. These studies have been registered at www.clinicaltrials.gov NCT00971321 and NCT00964158. PMID:26176592

  2. Excretion of 14C-labeled cyanide in rats exposed to chronic intake of potassium cyanide

    SciTech Connect

    Okoh, P.N.

    1983-09-15

    The excretion of an acute dose of 14C-labeled cyanide in urine, feces, and expired air was studied in rats exposed to daily intake of unlabeled KCN in the diet for 6 weeks. Urinary excretion was the main route of elimination of cyanide carbon in these rats, accounting for 83% of the total excreted radioactivity in 12 hr and 89% of the total excreted radioactivity in 24 hr. The major excretion metabolite of cyanide in urine was thiocyanate, and this metabolite accounted for 71 and 79% of the total urinary activity in 12 hr and 24 hr, respectively. The mean total activity excreted in expired air after 12 hr was only 4%, and this value did not change after 24 hr. Of the total activity in expired air in 24 hr, 90% was present as carbon dioxide and 9% as cyanide. When these results were compared with those observed for control rats, it was clear that the mode of elimination of cyanide carbon in both urine and breath was not altered by the chronic intake of cyanide.

  3. Pharmacokinetic profile of rizatriptan 10-mg tablet and 10-mg orally disintegrating tablet administered with or without water in healthy subjects: an open-label, randomized, single-dose, 3-period crossover study.

    PubMed

    Swan, Suzanne K; Alcorn, Harry; Rodgers, Anthony; Hustad, Carolyn M; Ramsey, Karen E; Woll, Susan; Skobieranda, Franck

    2006-02-01

    This open-label, 3-period crossover study compared the plasma concentration profiles of rizatriptan tablet, orally disintegrating tablet with water (ODTc), and ODT without water (ODTs) in 24 healthy volunteers aged 18 to 45 years. At each period, subjects received a single dose of either 10-mg rizatriptan tablet, 10-mg rizatriptan ODTs, or 10-mg rizatriptan ODTc. The authors hypothesized that ODTc has a greater geometric mean AUC(0-2h) than ODTs and that ODTc has a greater geometric mean AUC(0-1h) than tablet. A secondary end point was to compare the time of occurrence of the maximum rizatriptan plasma concentration (t(max)) of each dosing method. ODTc had a statistically significantly greater geometric mean AUC(0-2h) compared with ODTs (33.84 h x ng/mL vs 18.83 h x ng/mL; P < .001). ODTc had a slightly, but not statistically significantly, greater geometric mean AUC(0-1h) compared with rizatriptan tablet (17.07 h x ng/mL vs 13.32 h x ng/mL). The median t(max) was 0.67 hours for ODTc and tablet and 1.33 hours for ODTs. ODTc showed a slightly, but not significantly, faster rate of absorption compared with tablet. ODTs with water had a faster rate of absorption than ODTc. Future studies are needed to determine whether this pharmacokinetic difference produces differential efficacy in a clinical setting. PMID:16432269

  4. The Excretion of Renal Cells Following Necrosis of the Distal Segment of the Nephron by Hexadi-Methrine Bromide

    PubMed Central

    Davies, D. J.; Kennedy, A.; Roberts, C.

    1969-01-01

    The rate of excretion of renal cells was determined in rats with necrosis of the distal convoluted tubules and broad ascending limbs of the loops of Henle caused by injection of hexadimethrine bromide. The magnitude and the duration of abnormal cell excretion were correlated both with the dose of hexadimethrine and with the degree of damage that was evident on histological examination of the kidney. In general cell excretion studies provided a satisfactory indication of the degree of renal damage but the smallest lesions did not cause a significant increase in cell excretion and occasionally a rat with a very large lesion failed to show an increase in cell excretion rate. The changes in excretion rates observed in the present experiments were less than those found previously in animals with necrosis of proximal convoluted tubules caused by mercuric chloride. This is probably due firstly to the smaller number of cells in the distal nephron and secondly to the toxin causing disintegration of many of the cells. These findings have implications for the investigation of analgesic nephrotoxicity by measurement of urinary cell excretion rates. In order to appreciate the significance of increases in renal cell excretion following administration of various substances their site of action and the type of cell damage that they cause must first be established. ImagesFigs. 1-4 PMID:5792904

  5. Side effects in the neonate from psychotropic agents excreted through breast-feeding.

    PubMed

    Ananth, J

    1978-07-01

    Neuroleptics, antidepressants, lithium, anxiolytics, and hypnotics may be excreted in breast milk. Because of the danger to the neonate, drugs such as diazepam, lithium, bromides, reserpine, and opium alkaloids should not be given to lactating women, and barbiturates, haloperidol, and penfluridol should be administered with caution. The side effects produced as a result of breast-feeding of the infant by mothers consuming psychotropic drugs are reviewed and possible preventive measures are discussed. PMID:665791

  6. Effect of dietary caffeine and theophylline on urinary calcium excretion in the adult rat.

    PubMed

    Whiting, S J; Whitney, H L

    1987-07-01

    The chronic effects of dietary caffeine or theophylline on urinary calcium excretion were investigated in the adult male rat. When caffeine was added at two concentrations, 0.75 and 1.50 g/kg diet, 24-h urinary calcium excretion rose 300 and 450% on d 7, and 200 and 330% on d 14, respectively. There were no changes in the 24-h urinary excretion of phosphate, sulfate, sodium and cAMP nor did urine volume change. The high dose of caffeine was compared to an equimolar dose of theophylline (1.39 g/kg diet) in both Wistar and Sprague-Dawley rats. Urinary calcium excretion in theophylline-treated rats was significantly greater than in caffeine-treated rats on all sampling days and in both strains of rat; the calciuric effect lasted at least 22 d. When rats were given indomethacin (3.3 mg/kg diet) the calciuria induced by caffeine and theophylline was abolished, and sodium excretion in all groups was reduced by 35-50%, but urine volume was unchanged. The calciuria of methylxanthine feeding may result from a prostaglandin-mediated process distinct from diuresis. PMID:3612301

  7. Renal dopamine excretion in healthy volunteers after oral ingestion of L-dopa.

    PubMed

    Barthelmebs, M; Mbou, P; Stephan, D; Grima, M; Imbs, J L

    1993-01-01

    L-Dopa is converted to dopamine by aromatic-L-amino acid decarboxylase (AADC). In the kidney, proximal tubular epithelial cells are rich in AADC and urinary free dopamine excretion is a marker for endorenal extraneuronal dopamine synthesis. The urinary free dopamine excretion was analysed in a double-blind cross-over study after oral ingestion of L-Dopa or a placebo in five healthy volunteers. The drug ingestions were separated by one week's wash-out. Since in a preliminary study, two volunteers ingesting a single L-Dopa dose of 500 mg with breakfast experienced nausea, the five volunteers of the present study were given 300 mg L-Dopa (50 mg at 9 am with breakfast, 100 mg before lunch and 150 mg before dinner) without any adverse effects. L-Dopa induced an increase in 24-h urinary dopamine excretion (HPLC with electrochemical detection). Free urinary dopamine (1900 micrograms/24 h) accounted for 0.8% of the daily oral L-Dopa dose and represented 10% of total urinary dopamine excretion. L-Dopa treatment had no significant effect on mean ambulatory arterial blood pressure and heart rate measured from 9 am to 6 pm (Spacelabs) or on 24 h urinary water and sodium excretion. PMID:8458598

  8. [Hepatoduodenal circulation and excretion of the new GABA derivative citrocard].

    PubMed

    Tiurenkov, I N; Perfilova, V N; Smirnova, L A; Riabukha, A F; Suchkov, E A; Lebedeva, S A

    2013-01-01

    Pharmacokinetic investigation of a new gamma-aminobutyric acid (GABA) derivative cirtocard showed that, upon the intravenous introduction, the drug is determined in high concentrations in organs of elimination--the liver and kidneys. The tissue accessibility amounts to 1.341 for the liver and 4.053 for the kidneys and the separation factor is 1.041 for the liver and 4.486 for the kidneys. The study of drug excretion showed that cirtocard is determined in the urine for 48 h, its nephritic clearance being 0.047 L/h and extra-nephritic clearance, 0.33 L/h. For the unchanged substance, a large significance ofhepatoduodenal circulation is low probable, since no more than 1 - 2% of the introduced dose was isolated with bile over entire experiment. It is established that the removal of the unchanged substance does not exceed 10% of the introduced dose. There is high probability of hepatoduodenal circulation and excretion of the preparation in the form of metabolites. PMID:23767103

  9. Excretion and metabolism of flunarizine in rats and dogs.

    PubMed

    Meuldermans, W; Hendrickx, J; Hurkmans, R; Swysen, E; Woestenborghs, R; Lauwers, W; Heykants, J

    1983-01-01

    The excretion and metabolism of (E)-1-[bis(4-fluorophenyl)methyl]-4-(3-phenyl-2-propenyl)piperazine dihydrochloride (flunarizine hydrochloride, R 14 950, Sibelium) were studied after single oral doses in rats and dogs, using tritium-labelled as well as 14C-labelled drug. Flunarizine was well absorbed in both species. The mass balance for the unchanged drug and its major metabolites in urine, bile and faeces, as estimated with radio-HPLC, ALLOWED an explanation of the differences observed for the excretion pattern of the radioactivity in flunarizine-14C and flunarizine-3H dosed rats, and in male and female rats. Main metabolic pathway in male rats was the oxidative N-dealkylation resulting in bis(4-fluorophenyl)methanol and a number of complementary metabolites of the cinnamylpiperazine moiety, of which hippuric acid was the main one. In female rats and male dogs, however, hydroxy-flunarizine was the main metabolite, resulting from the aromatic hydroxylation of the phenyl ring of the cinnamyl moiety. Enterohepatic circulation of bis(4-fluorophenyl)methanol and hydroxy-flunarizine was proved by "donor-acceptor" coupling in rats; in bile and urine, these two metabolites were present mainly as glucuronides. The glucuronide of hydroxy-flunarizine was also the main plasma metabolite in dogs. PMID:6685491

  10. Development of a kinetic model and calculation of radiation dose estimates for sodium iodide-{sup 131}I in athyroid individuals

    SciTech Connect

    Rodriguez, M.

    1997-07-01

    The treatment for some thyroid carcinomas involves surgically removing the thyroid gland and administering the radiopharmaceutical Sodium iodide-{sup 131}I (NaI). A diagnostic dose of NaI is given to the patient to determine if remnant tissue from the gland remains or larger doses are administered in order to treat the malignant tissue. Past research regarding NaI uptake and retention in euthyroid individuals (normal functioning thyroid) reveal that radioiodine concentrates mainly in the thyroid tissue and the remaining material is excreted from the body. The majority of radioiodine in athyroid (without thyroid) individuals is also eliminated from the body; however, there has been recent evidence of a long-term retention phase for individuals with no radioiodine concentrating tissue. The general purpose of this study was to develop a kinetic model and estimate the absorbed dose to athyroid individuals regarding the distribution and retention of NaI.

  11. Effect of metal chelators on excretion and tissue levels of essential trace elements

    SciTech Connect

    Tandon, S.K.; Jain, V.K.; Mathur, A.K.

    1984-10-01

    The influence of one, three, and six doses of ethylenediaminetetraacetic acid (EDTA) diethylenetriaminepentaacetic acid (DTPA), and triethylenetetramine (TETA) on the urinary excretion of Ca, Cu, Fe, and Zn, and on their levels in liver, kidneys, heart, and serum in rats, was investigated to ascertain their suitability in amelioration of metal intoxication. While excretion of all the essential trace metals examined was enhanced significantly, the tissue and serum levels of some of them either increased or decreased after administration of the chelators. The results suggest depletion of some of the endogenous trace metals from the body and their intertissue redistribution following treatment with these chelating agents.

  12. Antidiuretic hormone excretion at high altitude.

    PubMed

    Harber, M J; Williams, J D; Morton, J J

    1981-01-01

    Urinary excretion of electrolytes, creatinine, urea, and antidiuretic hormone--measured as arginine vasopressin (AVP) by radioimmunoassay--was investigated in eight Himalayan mountaineers during ascent on foot from 1900- 5400 m. Specimens were collected from each individual whenever urine was voided, preserved with 1% boric acid, and subsequently pooled to give samples representative of 24-h collections. AVP was found to be reasonably stable under simulated conditions of storage. In all subjects, the observed AVP excretion rates were mostly in the lower region of the normal range and there was generally no correlation with altitude, urine osmolality, electrolyte excretion, or occurrence of AMS symptoms--even in a fatal case of cerebral oedema. It is concluded that AVP does not play a primary role in the changes in fluid balance which accompany either acclimatization to high altitude or the onset of AMS. PMID:7213286

  13. Pharmacokinetics of triclopyr (3,5,6-trichloro-2-pyridinyloxyacetic acid) in the beagle dog and rhesus monkey: perspective on the reduced capacity of dogs to excrete this organic acid relative to the rat, monkey, and human.

    PubMed

    Timchalk, C; Nolan, R J

    1997-06-01

    The pharmacokinetics of triclopyr (3,5,6-trichloro-2-pyridinyloxyacetic acid) were measured in the beagle dog and rhesus monkey and compared with the kinetics observed in rats and humans. In addition, studies were conducted in anesthetized dogs to better understand the mechanism by which [14C]triclopyr is eliminated in this species. Triclopyr was dissolved in distilled water, and administered as a single oral dose of 0.5, 5, or 20 mg/kg to three male dogs. A single male rhesus monkey was given an intravenous dose of 30 mg [14C]triclopyr/kg body wt on two occasions separated by 10 days. Anesthetized male dogs, were implanted with venous, arterial, and urethral catheters and given increasing amounts of triclopyr to produce plasma triclopyr levels ranging from 0.3 to 27 microg eq/mL. In the monkey, triclopyr was rapidly eliminated from the plasma (t1/2 = 6.3 hr) with >95% of the urinary 14C activity excreted within 24 hr postdosing. In the dog, orally administered triclopyr was rapidly and effectively absorbed at every dose level with virtually all of it excreted in the urine by 72 hr postdosing. However, the kinetics were slightly nonlinear, and the fraction of the dose excreted in the urine decreased with increasing dose. Several nonlinear processes may collectively contribute to the modest nonlinear pharmacokinetics in the dog. Plasma protein binding of triclopyr in the dog ranged from 94 to 99%, was nonlinear, and was an important determinant in the renal clearance of triclopyr. The nonlinear plasma protein binding indicates that glomerular filtration became disproportionately more important as plasma triclopyr concentration increased. There was good evidence for a high-affinity low-capacity active-secretory process that was saturated by low plasma triclopyr concentrations. As plasma triclopyr concentrations increased, tubular reabsorption begins to exceed secretion, resulting in decreased renal clearance. The volume of distribution, normalized for body weight

  14. Relation between creatinine and uric acid excretion.

    PubMed Central

    Nishida, Y

    1992-01-01

    The relation between creatinine and uric acid metabolism was analysed in 77 male patients with primary gout and 62 healthy male subjects. Significant positive correlations between 24 hour urinary creatinine and uric acid excretion were shown in both groups. The mean urinary creatinine and uric acid excretions in the patients with gout were significantly increased as compared with those of normal male controls. These results suggest that there is a close correlation between creatinine and uric acid synthesis. In addition, it seems that accelerated uric acid synthesis seen in some patients with gout is due to increased creatinine synthesis. PMID:1540011

  15. Dissipation of Antimicrobials in Feedlot Manure Compost after Oral Administration versus Fortification after Excretion.

    PubMed

    Amarakoon, Inoka D; Zvomuya, Francis; Sura, Srinivas; Larney, Francis J; Cessna, Allan J; Xu, Shanwei; McAllister, Tim A

    2016-03-01

    Fortification of manure with antimicrobials is one approach to studying their dissipation. However, fortified antimicrobials may not accurately model dissipation that occurs after antimicrobials have been administered to livestock in feed and excreted in manure. This study examined the dissipation of antimicrobials excreted in manure versus those added directly to manure (fortified). Steers were fed a diet containing (kg feed) (i) 44 mg chlortetracycline, (ii) 44 mg each of chlortetracycline and sulfamethazine, (iii) 11 mg tylosin, and (iv) no antimicrobials (control). Fortified antimicrobial treatments were prepared by adding antimicrobials to control manure. Manure was composted for 30 d, sampled every 2 to 3 d, and analyzed for antimicrobials and compost properties. Antimicrobial dissipation followed first-order kinetics. The dissipation rate constant was significantly greater (based on 95% confidence limit) for excreted (0.29-0.54 d) than for fortified chlortetracycline (0.11-0.13 d). In contrast, dissipation rate constants were significantly greater for fortified sulfamethazine (0.47 d) and tylosin (0.31 d) than when the same antimicrobials were excreted (0.08 and 0.07 d, respectively). On average, 85 to 99% of the initial antimicrobial concentrations in manure were dissipated after 30 d of composting. The degree of dissipation was greater ( < 0.0001) for fortified (99%) than for excreted tylosin (85%). Composting can be used to reduce environmental loading of antimicrobials before field application of beef cattle manure. Dissipation rates of fortified antimicrobials during manure composting may not accurately reflect those of antimicrobials that are consumed and excreted by cattle. PMID:27065397

  16. Interaction between the renal excretion rates of beta 2-microglobulin and tobramycin in man.

    PubMed

    Vree, T B; Zweens, K; Huige, P J; Guelen, P J; Jongman-Nix, B

    1984-03-27

    The renal excretion rate of beta 2-microglobulin in man is 127 +/- 98 ng/min at alkaline urine pH (pH 7). Tobramycin, up to intravenous doses of 160 mg (2 mg/kg) does not increase the renal excretion rate of beta 2-microglobulin. Tobramycin must have less affinity than gentamicin for the tubular system for active reabsorption of amino groups containing organic compounds. Due to this reduced affinity tobramycin will be absorbed less by the proximal tubular cells, which may be one of the reasons for tobramycin being less toxic than gentamicin. beta 2-Microglobulin excretion can be used as a parameter for the relative binding affinity of aminoglycosides. PMID:6370509

  17. Kinetics of Satratoxin G Tissue Distribution and Excretion Following Intranasal Exposure in the Mouse

    PubMed Central

    Amuzie, Chidozie J.; Islam, Zahidul; Kim, Jae Kyung; Seo, Ji-Hyun; Pestka, James J.

    2010-01-01

    Intranasal exposure of mice to satratoxin G (SG), a macrocyclic trichothecene produced by the indoor air mold Stachybotrys chartarum, selectively induces apoptosis in olfactory sensory neurons (OSNs) of the nose and brain. The purpose of this study was to measure the kinetics of distribution and clearance of SG in the mouse. Following intranasal instillation of female C57B16 mice with SG (500 μg/kg bw), the toxin was detectable from 5 to 60 min in blood and plasma, with the highest concentrations, 30 and 19 ng/ml, respectively, being observed at 5 min. SG clearance from plasma was rapid and followed single-compartment kinetics (t1/2 = 20 min) and differed markedly from that of other tissues. SG concentrations were maximal at 15–30 min in nasal turbinates (480 ng/g), kidney (280 ng/g), lung (250 ng/g), spleen (200 ng/g), liver (140 ng/g), thymus (90 ng/g), heart (70 ng/g), olfactory bulb (14 ng/g), and brain (3 ng/g). The half-lives of SG in the nasal turbinate and thymus were 7.6 and 10.1 h, respectively, whereas in other organs, these ranged from 2.3 to 4.4 h. SG was detectable in feces and urine, but cumulative excretion over 5 days via these routes accounted for less than 0.3% of the total dose administered. Taken together, SG was rapidly taken up from the nose, distributed to tissues involved in respiratory, immune, and neuronal function, and subsequently cleared. However, a significant amount of the toxin was retained in the nasal turbinate, which might contribute to SG’s capacity to evoke OSN death. PMID:20466779

  18. D-penicillamine does not increase urinary bismuth excretion in patients treated with tripotassium dicitrato bismuthate.

    PubMed Central

    Nwokolo, C U; Pounder, R E

    1990-01-01

    Twenty-four urinary bismuth excretion was measured in five patients who had been treated with tripotassium dicitrato bismuthate, before and after single 1 g oral dose of D-penicillamine. Before dosing with D-penicillamine, the median 24 h urinary bismuth output was 55 micrograms 24 h-1 (range 17-156 micrograms 24 h-1) and following dosing with D-penicillamine the median 24 h urinary bismuth output was 53 micrograms 24 h-1 (range 12-156 micrograms 24 h-1). D-penicillamine does not facilitate the urinary excretion of bismuth, hence it is unsuitable for use as an oral chelator in patients with bismuth intoxication. PMID:2291879

  19. Comparison of celecoxib metabolism and excretion in mouse, rabbit, dog, cynomolgus monkey and rhesus monkey.

    PubMed

    Paulson, S K; Zhang, J Y; Jessen, S M; Lawal, Y; Liu, N W; Dudkowski, C M; Wang, Y F; Chang, M; Yang, D; Findlay, J W; Berge, M A; Markos, C S; Breau, A P; Hribar, J D; Yuan, J

    2000-07-01

    1. The metabolism and excretion of celecoxib, a specific cyclooxygenase 2 (COX-2) inhibitor, was investigated in mouse, rabbit, the EM (extensive) and PM (poor metabolizer) dog, and rhesus and cynomolgus monkey. 2. Some sex and species differences were evident in the disposition of celecoxib. After intravenous (i.v.) administration of [14C]celecoxib, the major route of excretion of radioactivity in all species studied was via the faeces: EM dog (80.0%), PM dog (83.4%), cynomolgus monkey (63.5%), rhesus monkey (83.1%). After oral administration, faeces were the primary route of excretion in rabbit (72.2%) and the male mouse (71.1%), with the remainder of the dose excreted in the urine. After oral administration of [14C]celecoxib to the female mouse, radioactivity was eliminated equally in urine (45.7%) and faeces (46.7%). 3. Biotransformation of celecoxib occurs primarily by oxidation of the aromatic methyl group to form a hydroxymethyl metabolite, which is further oxidized to the carboxylic acid analogue. 4. An additional phase I metabolite (phenyl ring hydroxylation) and a glucuronide conjugate of the carboxylic acid metabolite was produced by rabbit. 5. The major excretion product in urine and faeces of mouse, rabbit, dog and monkey was the carboxylic acid metabolite of celecoxib. PMID:10963063

  20. Urinary glucaric acid excretion in rheumatoid arthritis: influence of disease activity and disease modifying drugs.

    PubMed Central

    Addyman, R; Beyeler, C; Astbury, C; Bird, H A

    1996-01-01

    OBJECTIVE: To examine if a correlation exists between cytochrome P-450 enzyme induction and disease activity in patients with rheumatoid arthritis (RA), measuring urinary excretion of D-glucaric acid (GA) as an index of phase II drug metabolism. METHODS: Patients with RA were treated with sulphasalazine, sodium aurothiomalate, or D-penicillamine in standard dose regimens, for 24 weeks. Patients with ankylosing spondylitis (AS) or non-inflammatory arthritis (NIA) acted as controls. The urinary GA:creatinine ratio was measured at 0, 12, and 24 weeks of treatment. RESULTS: Patients with RA had a slightly greater urinary GA:creatinine ratio than patients with AS or NIA at baseline; this increased during treatment with disease modifying antirheumatic drugs (DMARDs). Sulphasalazine treatment had a greater effect on GA excretion than sodium aurothiomalate or D-penicillamine; this difference was statistically significant between weeks 0 and 12 (p = 0.01). Gamma glutamyltranspeptidase concentration showed a weak correlation with GA excretion between weeks 0 and 12 (p = 0.03), but all other measurements of changes in disease activity (plasma viscosity, C reactive protein, platelets, and articular index) were found not to correlate with GA excretion between weeks 0-12 or 0-24. CONCLUSION: The increased excretion of GA in patients with RA receiving DMARD treatment is probably the result of an indirect effect on hepatic metabolism bearing no relationship to disease activity. PMID:8774168

  1. Plasma disappearance, urine excretion, and tissue distribution of ribavirin in rats and rhesus monkeys

    SciTech Connect

    Ferrara, E.A.; Oishi, J.S.; Wannemacher, R.W. Jr.; Stephen, E.L.

    1981-06-01

    Ribavirin has been shown to have broad-spectrum antiviral. To study its tissue distribution and disappearance rate, a single dose of 10 mg/kg which contained 10 microCi of (14C)ribavirin was injected intravenously into rhesus monkeys and intramuscularly into monkeys and rats. Except for peak plasma concentrations and the initial phases of the plasma disappearance and urine excretion curves, no significant difference was observed between plasma, tissue, or urine values for intramuscularly or intravenously injected monkeys. Plasma disappearance curves were triphasic; plasma concentrations of ribavirin were similar for both monkeys and rats. Rats excreted ribavirin in the urine more rapidly and to a greater extent (82% excreted in 24 h) than did monkeys (60% excreted in 72 h). In the rat, only 3% of the injected (14C)ribavirin was detected in expired CO2. Therefore, for both species, urine was the major route for the elimination of labeled ribavirin and its metabolites from the body. In monkeys, the amount of parent drug in blood cells increased through 48 h and remained stable for 72 h, whereas in rats, ribavirin decreased at a rate similar to the plasma disappearance curve. Concentrations of ribavirin at 8 h were consistently higher in monkeys than in rats for all tissues except the brain. Thus, these differences in blood cellular components and organ content and in urine excretion suggested that there was greater tissue retention of ribavirin in monkeys than in rats.

  2. Effects of supplemental dietary calcium on quantitative and qualitative fecal fat excretion in man.

    PubMed

    Welberg, J W; Monkelbaan, J F; de Vries, E G; Muskiet, F A; Cats, A; Oremus, E T; Boersma-van Ek, W; van Rijsbergen, H; van der Meer, R; Mulder, N H

    1994-01-01

    Oral calcium supplementation is thought to be a useful interventional agent to decrease colon cancer risk. This is supposedly due, at least in part, to the binding of bile acids and fatty acids by calcium in the colon, thus prohibiting the damaging effects of these substances to the epithelium. To determine the effects of calcium supplementation on fecal fat excretion, 24 subjects kept a fat and calcium constant diet for one week and were supplemented with either 0, 2 or 4 g elemental calcium as calcium carbonate in a double-blind fashion. At the end of the week 72-hour feces was collected, and total fat, neutral fat, fatty acids and the ratio of polyunsaturated and saturated fatty acids (P/S ratio) were measured. Calcium dose-dependently increased the percentual excretion of total fat as related to fat intake: 6.8 +/- 0.9% during 0 g, 7.4 +/- 1.0% during 2 g and 10.2 +/- 1.4% during 4 g, r = 0.44, p = 0.03. This was due to increased fatty acid excretion, excretion of neutral fat was not affected, nor was the P/S ratio. It is concluded that calcium supplementation modestly increases fecal fatty acid excretion. No adverse metabolic effects are to be expected from this in case of long-term calcium supplementation in subjects at increased risk for colon cancer. PMID:7832578

  3. Whole-body retention, and urinary and fecal excretion of mercury after subchronic oral exposure to mercuric chloride in rats.

    PubMed

    Morcillo, M A; Santamaria, J

    1995-10-01

    The effects of long-term daily intake of mercury on its urinary and fecal excretion, whole-body retention, and blood concentration in male rats were observed. The animals were exposed to mercuric, chloride labeled with 203Hg via drinking water for 8 weeks (5, 50 and 500 microM Hg). 203Hg in urine, feces and blood was quantified. The blood mercury concentration did not keep a linear relationship with the increasing dose. The percentage of the total amount of mercury intake which is excreted by the fecal route in rats exposed to 500 microM Hg was significantly lower than in those exposed to 5 and 50 microM. The daily dose percentage of mercury excreted in urine increased with dose size. The results show that the absorption fraction of mercury through the gastrointestinal tract (30-40%) was higher than values previously reported. PMID:7580050

  4. Chemical synthesis of deuterated folate monoglutamate and in vivo assessment of urinary excretion of deuterated folates in man

    SciTech Connect

    Gregory, J.F. III; Toth, J.P.

    1988-04-01

    The synthesis and in vivo application of stable-isotopically labeled folic acid was investigated to devise methods suitable for studies of folate metabolism in human subjects. Glutamate-labeled tetradeutero-pteroylglutamic acid (d4-folic acid) was prepared by mixed anhydride coupling of N10-trifluoroacetylpteroic acid and dimethyl L-(3,3,4,4-2H4)glutamic acid, saponification in sodium deuteroxide, and chromatographic purification. Retention of the isotopic label was verified by proton NMR and mass spectrometry of the para-aminobenzoylglutamic acid product of C9-N10 bond cleavage. A method was devised for determination of of isotopic enrichment of urinary d4-folates derived from orally administered d4-folic acid using affinity chromatographic purification, chemical cleavage of the C9-N10 bond, HPLC isolation of the p-(2H4)aminobenzoylglutamate product, followed by negative-ion chemical-ionization gas chromatography/mass spectrometry. Data concerning the urinary excretion of d4-folates derived from an oral dose of d4-folic acid in an adult human are presented.

  5. Increased urinary excretion of platelet activating factor in mice with lupus nephritis

    SciTech Connect

    Macconi, D.; Noris, M.; Benfenati, E.; Quaglia, R.; Pagliarino, G. ); Remuzzi, G. Ospedali Riuniti di Bergamo )

    1991-01-01

    Platelet activating factor (PAF) is present in urine from humans and experimental animals in normal conditions. Very little is known about changes in PAF urinary excretion under pathologic conditions and no data are available about the origin of PAF in the urine. In the present study we explored the possibility that immunologic renal disease is associated with an increase in PAF urinary excretion using gas chromatography-mass spectrometry technique. To clarify the renal or extrarenal origin of urinary PAF we evaluated whether exogenously administered PAF (1-(1{prime},2{prime}-{sup 3}H)alkyl) is filtered through the glomerulus and excreted in the urine. The results show that: (1) urine from mice with lupus nephritis in the early phase of the disease contained amounts of PAF comparable to those excreted in normal mouse urine, (2) PAF levels increased when animals started to develop high grade proteinuria, (3) after intravenous injection of ({sup 3}H) PAF In nephritic mice, a negligible amount of ({sup 3}H) ether lipid, corresponding to ({sup 3}H)1-alkyl -2-acyl-3-phosphocholine (alkyl-2-acyl-GPC), was recovered from the 24 h urine extract.

  6. Lanthanum Carbonate Reduces Urine Phosphorus Excretion: Evidence of High-Capacity Phosphate Binding

    PubMed Central

    Pennick, Michael; Poole, Lynne; Dennis, Kerry; Smyth, Michael

    2012-01-01

    The effectiveness of phosphate binders can be assessed by evaluating urinary phosphorus excretion in healthy volunteers, which indicates the ability of the phosphate binder to reduce gastrointestinal phosphate absorption. Healthy volunteers were enrolled into one of five separate randomized trials; four were open label and one double blind. Following a screening period of <28 days, participants received differing tablets containing lanthanum carbonate [LC, 3000 mg/day of elemental lanthanum (in one study other doses were also used)]. Participants received a standardized phosphate diet and remained in the relevant study center throughout the duration of each treatment period. The end point in all studies was the reduction in urinary phosphorus excretion. Reductions in mean 24-h urinary phosphorus excretion in volunteers receiving a lanthanum dose of 3000 mg/day were between 236 and 468 mg/day over the five separate studies. These data in healthy volunteers can be used to estimate the amount of reduction of dietary phosphate absorption by LC. The reduction in 24-h urinary phosphorus excretion per tablet was compared with published data on other phosphate binders. Although there are limitations, evidence suggests that LC is a very effective phosphate binder in terms of binding per tablet. PMID:22250993

  7. Absorption, distribution, metabolism, and excretion of the novel antibacterial prodrug tedizolid phosphate.

    PubMed

    Ong, Voon; Flanagan, Shawn; Fang, Edward; Dreskin, Howard J; Locke, Jeffrey B; Bartizal, Kenneth; Prokocimer, Philippe

    2014-08-01

    Tedizolid phosphate is a novel antibacterial prodrug with potent activity against Gram-positive pathogens. In vitro and in vivo studies demonstrated that the prodrug is rapidly converted by nonspecific phosphatases to the biologically active moiety tedizolid. Single oral dose radiolabeled (14)C-tedizolid phosphate kinetic studies in human subjects (100 µCi in 204 mg tedizolid phosphate free acid) confirmed a rapid time to maximum tedizolid concentration (Tmax, 1.28 hours), a long terminal half-life (10.6 hours), and a Cmax of 1.99 µg/ml. Metabolite analysis of plasma, fecal, and urine samples from rats, dogs, and humans confirmed that tedizolid is the only measurable metabolite in plasma after intravenous (in animals only) or oral administration and that tedizolid sulfate is the major metabolite excreted from the body. Excellent mass balance recovery was achieved and demonstrated that fecal excretion is the predominant (80-90%) route of elimination across species, primarily as tedizolid sulfate. Urine excretion accounted for the balance of drug elimination but contained a broader range of minor metabolites. Glucuronidation products were not detected. Similar results were observed in rats and dogs after both intravenous and oral administration. The tedizolid metabolites showed less potent antibacterial activity than tedizolid. The observations from these studies support once daily dosing of tedizolid phosphate and highlight important metabolism and excretion features that differentiate tedizolid phosphate from linezolid. PMID:24875463

  8. Targeted Lung Delivery of Nasally Administered Aerosols

    PubMed Central

    Tian, Geng; Hindle, Michael; Longest, P. Worth

    2014-01-01

    Using the nasal route to deliver pharmaceutical aerosols to the lungs has a number of advantages including co-administration during non-invasive ventilation. The objective of this study was to evaluate the growth and deposition characteristics of nasally administered aerosol throughout the conducting airways based on delivery with streamlined interfaces implementing two forms of controlled condensational growth technology. Characteristic conducting airways were considered including a nose-mouth-throat (NMT) geometry, complete upper tracheobronchial (TB) model through the third bifurcation (B3), and stochastic individual path (SIP) model to the terminal bronchioles (B15). Previously developed streamlined nasal cannula interfaces were used for the delivery of submicrometer particles using either enhanced condensational growth (ECG) or excipient enhanced growth (EEG) techniques. Computational fluid dynamics (CFD) simulations predicted aerosol transport, growth and deposition for a control (4.7 μm) and three submicrometer condensational aerosols with budesonide as a model insoluble drug. Depositional losses with condensational aerosols in the cannula and NMT were less than 5% of the initial dose, which represents an order-of-magnitude reduction compared to the control. The condensational growth techniques increased the TB dose by a factor of 1.1–2.6x, delivered at least 70% of the dose to the alveolar region, and produced final aerosol sizes ≥2.5 μm. Compared to multiple commercial orally inhaled products, the nose-to-lung delivery approach increased dose to the biologically important lower TB region by factors as large as 35x. In conclusion, nose-to-lung delivery with streamlined nasal cannulas and condensational aerosols was highly efficient and targeted deposition to the lower TB and alveolar regions. PMID:24932058

  9. Excretion of bisphenol A into rat milk.

    PubMed

    Okabayashi, Ken; Watanabe, Toshi

    2010-03-01

    Bisphenol A (BPA), an endocrine-disrupting chemical, is widely used in the production of polycarbonate plastic and epoxy resins. This study analyzed the BPA concentration in rat milk, in order to assess the risk of BPA transfer to the offspring via milk. The rats ingested BPA by oral administration or by drinking the water in a polycarbonate bottle, and the milk samples were collected using an automated experimental milker. The BPA concentration in the samples of milk, drinking water, and food was analyzed by LC/MS. In the case of milk samples obtained from rats injected with BPA at 2, 4, 8, and 24 h prior to milking, the BPA concentrations were 0.462 +/- 0.182 ppm, 0.138 +/- 0.0185 ppm, 0.080 +/- 0.0197 ppm, and 0.0232 +/- 0.0051 ppm, respectively. Also, in the cases of the water sample left in polycarbonate bottle and the milk sample obtained from rats provided it as drinking water, the concentrations of BPA were 0.000332 +/- 0.00015 ppm and 0.0184 +/- 0.0050 ppm, respectively. The results indicate that the BPA administered to the dams was transferred to their milk, and that BPA concentration in milk was higher at the early period after the single bolus dose. Additionally, these results reveal that sequential elution of BPA from polycarbonate containers in a much diluted form would undergo bioaccumulation in dams and likely be transferred to pups via milk in a much concentrated form. PMID:20163291

  10. Disposition of 2-(2-quinolyl)-1,3-indandione (D. C. , yellow No. 11) in rats dosed orally or intravenously

    SciTech Connect

    El Dareer, S.M.; Kalin, J.R.; Tillery, K.F.; Hill, D.L.

    1988-01-01

    The disposition of 2-(2-quinolyl)-1,3-indandione (D. C. yellow No. 11, DCY) in male Fischer rats dosed intravenously or by feeding was determined. For rats given (/sup 14/C)DCY in the feed (0.00044-0.41% of the diet), recovery of radioactivity during the 24-h dosing period and the 72-h period thereafter ranged from 89.1 to 93.9% for feces and from 4.98 to 6.25 for urine. Tissues contained only trace amounts. Following intravenous dosing with (/sup 14/C)DCY (0.93 mg/kg), radioactivity distributed readily into most tissues; maximum amounts were present at 5 min, the earliest time of assay. Maximum amounts of radioactivity in fat, skin, and gut tissue, however, were present at 30 min after dosing. These three tissues also had relatively long alpha phases for the elimination of radioactivity. In 24 h after intravenous dosing, rats excreted 81.1% of the dose in the feces and 16.0% of the dose in the urine. For rats fitted with biliary cannulas, 54.5% of the dose, all of which was metabolites of (/sup 14/C), was recovered in the bile in 4 h. Associated with the rapid and extensive biliary excretion of metabolites of intravenously administered (/sup 14/C)DCY was the appearance of large amounts of radioactivity in the feces and also, at intermediate time points, in the liver, gut contents, and gut tissue. In conclusion, rats rapidly distribute, metabolize, and excrete (/sup 14/C)DCY.

  11. Disposition of 2-(2-quinolyl)-1,3-indandione (D. C. yellow number11) in rats dosed orally or intravenously

    SciTech Connect

    el Dareer, S.M.; Kalin, J.R.; Tillery, K.F.; Hill, D.L.

    1988-01-01

    The disposition of 2-(2-quinolyl)-1,3-indandione (D. C. yellow number11, DCY) in male Fischer rats dosed intravenously or by feeding was determined. For rats given (/sup 14/C)DCY in the feed (0.00044-0.41% of the diet), recovery of radioactivity during the 24-h dosing period and the 72-h period thereafter ranged from 89.1 to 93.9% for feces and from 4.98 to 6.25 for urine. Tissues contained only trace amounts. Following intravenous dosing with (/sup 14/C)DCY (0.93 mg/kg), radioactivity distributed readily into most tissues; maximum amounts were present at 5 min, the earliest time of assay. Maximum amounts of radioactivity in fat, skin, and gut tissue, however, were present at 30 min after dosing. These three tissues also had relatively long alpha phases for the elimination of radioactivity. In 24 h after intravenous dosing, rats excreted 81.1% of the dose in the feces and 16.0% of the dose in the urine. For rats fitted with biliary cannulas, 54.5% of the dose, all of which was metabolites of (/sup 14/C)DCY, was recovered in the bile in 4 h. Associated with the rapid and extensive biliary excretion of metabolites of intravenously administered (/sup 14/C)DCY was the appearance of large amounts of radioactivity in the feces and also, at intermediate time points, in the liver, gut contents, and gut tissue. In conclusion, rats rapidly distribute, metabolize, and excrete (/sup 14/C)DCY.

  12. Absorption, metabolism and excretion of flavanones from single portions of orange fruit and juice and effects of anthropometric variables and contraceptive pill use on flavanone excretion

    PubMed Central

    Brett, Gary M.; Hollands, Wendy; Needs, Paul W.; Teucher, Birgit; Dainty, Jack R.; Davis, Barry D.; Brodbelt, Jennifer S.; Kroon, Paul A.

    2012-01-01

    Oranges are rich sources of flavonoids that are bioactive and may protect against age-related diseases. The absorption of orange flavanones may be affected by factors such as processing and subject anthropometric variables, and the bioactivity of the absorbed phytochemicals depends on how they are metabolised during absorption. In a randomised cross-over study, twenty subjects consumed a single portion of orange fruit (150 g) or juice (300 g) that contained the flavanones narirutin and hesperidin, and an additional 109 subjects across a broad age range (18–80 years) consumed the juice. Flavanone metabolites were measured in regularly collected samples of plasma and urine. After consumption of fruit or juice, flavanone conjugates, but not the aglycones, were detected in plasma and urine. The flavanone conjugates were shown to include the 7- and 4′-O-monoglucuronides of naringenin, the 7- and 3′-O-monoglucuronides of hesperetin, two hesperetin diglucuronides and a hesperetin sulfo-glucuronide, but no aglycones or rutinosides. Analysis of the plasma pharmacokinetic and urinary excretion data on a dose-adjusted basis indicated no difference in absorption or excretion of either flavanone between the fruit and juice matrices. In the extended urinary excretion dataset the individual variation was very large (range 0–59 % urinary yield). There was a small but significant (P<0·05) decrease in the excretion of hesperetin (but not naringenin) with increasing age (P<0·05), but the effects of sex, BMI and contraceptive pill use were shown not to be associated with the variation in flavanone excretion. PMID:18710603

  13. Urinary excretion of arsenic following rice consumption.

    PubMed

    Meharg, A A; Williams, P N; Deacon, C M; Norton, G J; Hossain, M; Louhing, D; Marwa, E; Lawgalwi, Y; Taggart, M; Cascio, C; Haris, P

    2014-11-01

    Patterns of arsenic excretion were followed in a cohort (n = 6) eating a defined rice diet, 300 g per day d.wt. where arsenic speciation was characterized in cooked rice, following a period of abstinence from rice, and other high arsenic containing foods. A control group who did not consume rice were also monitored. The rice consumed in the study contained inorganic arsenic and dimethylarsinic acid (DMA) at a ratio of 1:1, yet the urine speciation was dominated by DMA (90%). At steady state (rice consumption/urinary excretion) ∼40% of rice derived arsenic was excreted via urine. By monitoring of each urine pass throughout the day it was observed that there was considerable variation (up to 13-fold) for an individual's total arsenic urine content, and that there was a time dependent variation in urinary total arsenic content. This calls into question the robustness of routinely used first pass/spot check urine sampling for arsenic analysis. PMID:25145278

  14. Absorption, biotransformation, and excretion of environmental chemicals.

    PubMed

    Oehme, F W

    1980-08-01

    Foreign chemicals are continually present in the environment of man and animals. Mammalian systems are in a constant state of balance-the intake compensated for by the outflow. The intake is largely determined by the route of exposure and the chemical characteristics of the environmental compound. Under normal conditions of exposure to small or moderate amounts of environmental chemicals, the system is capable of biotransforming and detoxifying such materials into compounds more easily handled by the mammalian system. These are largely converted to more water-soluble materials and excreted in the urine, bile, and less commonly through other excretory routes. In situations of massive exposure to foreign materials, or when repeated exposure to moderate amounts of chemicals results in accumulation in body systems, toxicoses may result. These are essentially an overwhelming of the biological mechanisms for detoxifying and excreting such materials. The hazard associated with environmental chemicals is greatly increased if a preexisting disease modifies the normal biological detoxification processes. Therapy to assist intoxicated individuals is largely aimed at increasing excretory processes and maintaining or restoring the physiological balance between the amount of environmental chemical absorbed and the level capable of being excreted. PMID:7408430

  15. Calculating drug doses.

    PubMed

    2016-09-01

    Numeracy and calculation are key skills for nurses. As nurses are directly accountable for ensuring medicines are prescribed, dispensed and administered safely, they must be able to understand and calculate drug doses. PMID:27615351

  16. Absorption and excretion of undegradable peptides: role of lipid solubility and net charge.

    PubMed

    Pappenheimer, J R; Karnovsky, M L; Maggio, J E

    1997-01-01

    Absorption and excretion of undegradable peptides were investigated with use of octapeptides synthesized from D-amino acids. D-Tyrosine was included in each peptide to permit labeling with 125I, D-glutamic acid or D-lysine were included to vary net electric charge and D-serine or D-leucine were included to vary lipid solubility. Peptides were administered parenterally or orally to normal rats drinking 5% glucose or maltose. Forty-five percent of a lipid-insoluble, negatively charged octapeptide added to the drinking fluid in milligram quantities was absorbed from the intestine and excreted intact in urine; 90% of this peptide was recovered in urine after parenteral injection. In contrast, lipophilic D-octapeptides were largely excreted in feces, even after subcutaneous injection; the amounts excreted in feces were correlated with oil/aqueous partition coefficients. Evidence is presented that lipophilic peptides entering liver cells combine with bile salts to form hydrophilic complexes that are secreted rapidly at high concentration in bile. At physiological concentrations of bile salts (5-40 mM) and nanomolar concentrations of peptide the binding is so complete that these undegradable peptides are rapidly cleared from liver to duodenal fluid in association with the bile salts. After reaching the ileum the bile salts are reabsorbed to blood, leaving the original lipophilic peptides to be excreted in the feces from which they can be extracted, purified and identified by high-pressure liquid chromatography. These mechanisms are discussed in relation to a) the paracellular absorption of peptides and other solutes by solvent drag and b) the delivery and fate of biologically active peptides. PMID:8996209

  17. Excretion pattern of co-planar and non-planar tetra- and hexa-chlorobiphenyls in ovine milk and faeces

    SciTech Connect

    Vrecl, Milka . E-mail: milka.vrecl@vf.uni-lj.si; Ursic, Matjaz; Pogacnik, Azra; Zupancic-Kralj, Lucija; Jan, Janja

    2005-04-15

    This study employed the gas chromatography with electron capture detection to determine residual levels and excretion patterns of two pairs of structurally diverse polychlorinated biphenyl (PCB) congeners (IUPAC Nos. 54, 80, 155, and 169) administered to lactating sheep by intramuscular injection. PCB levels and excretion patterns in blood, milk, and faeces were time-dependent and differed from the composition of PCB congeners administered. Lactational transfer substantially exceeded the faecal transfer. Between days 3 and 7, the amount of PCB congeners 54 and 169 excreted in milk was around 50- and 800-fold higher than the amount of these two congeners excreted via faeces. During the same period, the relative contribution of co-planar PCB congeners (80 and 169) in PCB pattern decreased in blood and increased in milk and faeces compared with non-planar PCBs (54 and 155). On day 3, the ratio PCB 169 to 54 was 7-fold higher in milk than in faeces. PCB congeners with log K{sub ow} values under 6.5 reached peaks of their excretion in milk within the first three days after administration, while the super-lipophilic PCB 169 congener with log K{sub ow} value of over 7 has not reached the plateau until day 10, but afterwards, its level remained relatively high throughout the observation period. During the 57-day follow-up period, the excretion of PCB 80, 155, and 169 in milk was 4.5-, 14-, and 46-fold greater compared with PCB 54. Differences in levels and patterns were explained with some physico-chemical properties of individual PCB congeners, such as lipophilicity, planarity, metabolic stability, sorption/diffusion properties.

  18. Human urinary excretion profile after smoking and oral administration of ( sup 14 C)delta 1-tetrahydrocannabinol

    SciTech Connect

    Johansson, E.; Gillespie, H.K.; Halldin, M.M. )

    1990-05-01

    The urinary excretion profiles of delta 1-tetrahydrocannabinol (delta 1-THC) metabolites have been evaluated in two chronic and two naive marijuana users after smoking and oral administration of ({sup 14}C)delta 1-THC. Urine was collected for five days after each administration route and analyzed for total delta 1-THC metabolites by radioactivity determination, for delta 1-THC-7-oic acid by high-performance liquid chromatography, and for cross-reacting cannabinoids by the EMIT d.a.u. cannabinoid assay. The average urinary excretion half-life of {sup 14}C-labeled delta 1-THC metabolites was calculated to be 18.2 +/- 4.9 h (+/- SD). The excretion profiles of delta 1-THC-7-oic acid and EMIT readings were similar to the excretion profile of {sup 14}C-labeled metabolites in the naive users. However, in the chronic users the excretion profiles of delta 1-THC-7-oic acid and EMIT readings did not resemble the radioactive excretion due to the heavy influence from previous Cannabis use. Between 8-14% of the radioactive dose was recovered in the urine in both user groups after oral administration. Lower urinary recovery was obtained both in the chronic and naive users after smoking--5 and 2%, respectively.

  19. [Excretion of zinc in lactating cows receiving various supply of zinc].

    PubMed

    Schwarz, W A; Kirchgessner, M

    1975-12-01

    Studies were carried out with 5 lactating cows receiving a semisynthetic diet to trace the pattern of zinc excretion in the faeces, urine and milk under conditions of Zn depletion and repletion. Faecal Zn concentrations were found to be drastically reduced during a 6-week period of Zn depletion. The Zn supply to the animals at different levels of Zn repletion (varying between 22 mg and 436 mg Zn per kg) was well reflected in the corresponding faecal Zn concentrations. Similarly, faecal Zn excretion expressed as the percentage of Zn supplied with the diet was shown to change with the level of Zn supply. In the range between 6 mg and 54 m Zn per kg of dietary dry matter the level of relative faecal Zn excretion increased from 42% to 56% whereas with higher Zn supplements (up to 436 mg/kg) only slight increases (up to 60%) were observed. This indicates that the organism exhibits a strong tendency to maintain a physiological balance; this tendency is all the more pronounced with increasing Zn depletion; thus after 19 weeks of Zn depletion as little as 25% of the administered amount of Zn was excreted in the faeces. The average minimum of urinary Zn concentrations was 0.25 mg Zn per litre. The Zn concentrations in urine were not found to be dependent on the Zn supply. The level of relative Zn excretion in the milk was markedly increased despite the reduced concentrations of milk Zn during the periods of Zn deficiency. At the beginning of Zn depletion rather more zinc was released with the milk than was taken up with the Zn deficient diet. The mean proportion of milk Zn in the total amount of dietary Zn over the 6-week depletion period was 91%. With Zn amounts of 22 mg, 54 mg, 87 mg, 108 mg, 130 mg and 436 mg per kg of diet 23.7%, 13.1%, 12.9%, 5.7%, 4.3%, and 1.7% of the dietary Zn were excreted with the milk. Thus, a relative decrease of Zn excretion in the milk was observed, i.e. relative to the level of Zn supplementation. PMID:1241940

  20. [Effect of methylxanthines on urinary prostaglandin E excretion of rats acutely loaded with salt and water (author's transl)].

    PubMed

    Takeuchi, K; Kogo, H; Aizawa, Y

    1981-04-01

    The effect of methylxanthines (theophylline, theobromine, caffeine) on urinary prostaglandin E (PGE) excretion in rats was investigated. Male rats, weighing 270-300g only were used. Food was withdrawn 3 hr before the experiment and water intake was free during the test period. In saline or water loaded experiments, 0.9%, 9% NaCl solution or water containing each drug was administered orally in a volume of 2.5 ml/100g. The urinary PGE was measured by bioassay using rat stomach fundus strip. In rats loaded with isotonic saline, the urinary PGE excretion was increased by methylxanthines and the greatest effect was seen with theophylline. The effect of theophylline on PGE excretion was evident in non-loaded and isotonic saline-loaded rats. In particular, the percentages of PGE, sodium and chloride in the urine were remarkably increased, as compared with findings in the control. In non-loaded and isotonic saline-loaded rats, the urinary PGE excretion induced by theophylline correlated significantly with the sodium and chloride excretion. These results suggest the participation of renal PGE in the effects of theophylline on kidney function. PMID:7286846

  1. Biological Monitoring of Human Exposure to Neonicotinoids Using Urine Samples, and Neonicotinoid Excretion Kinetics

    PubMed Central

    Harada, Kouji H.; Tanaka, Keiko; Sakamoto, Hiroko; Imanaka, Mie; Niisoe, Tamon; Hitomi, Toshiaki; Kobayashi, Hatasu; Okuda, Hiroko; Inoue, Sumiko; Kusakawa, Koichi; Oshima, Masayo; Watanabe, Kiyohiko; Yasojima, Makoto; Takasuga, Takumi; Koizumi, Akio

    2016-01-01

    Background Neonicotinoids, which are novel pesticides, have entered into usage around the world because they are selectively toxic to arthropods and relatively non-toxic to vertebrates. It has been suggested that several neonicotinoids cause neurodevelopmental toxicity in mammals. The aim was to establish the relationship between oral intake and urinary excretion of neonicotinoids by humans to facilitate biological monitoring, and to estimate dietary neonicotinoid intakes by Japanese adults. Methodology/Principal Findings Deuterium-labeled neonicotinoid (acetamiprid, clothianidin, dinotefuran, and imidacloprid) microdoses were orally ingested by nine healthy adults, and 24 h pooled urine samples were collected for 4 consecutive days after dosing. The excretion kinetics were modeled using one- and two-compartment models, then validated in a non-deuterium-labeled neonicotinoid microdose study involving 12 healthy adults. Increased urinary concentrations of labeled neonicotinoids were observed after dosing. Clothianidin was recovered unchanged within 3 days, and most dinotefuran was recovered unchanged within 1 day. Around 10% of the imidacloprid dose was excreted unchanged. Most of the acetamiprid was metabolized to desmethyl-acetamiprid. Spot urine samples from 373 Japanese adults were analyzed for neonicotinoids, and daily intakes were estimated. The estimated average daily intake of these neonicotinoids was 0.53–3.66 μg/day. The highest intake of any of the neonicotinoids in the study population was 64.5 μg/day for dinotefuran, and this was <1% of the acceptable daily intake. PMID:26731104

  2. Identifying plasma glycerol concentration associated with urinary glycerol excretion in trained humans.

    PubMed

    Nelson, Jeff L; Harmon, Molly E; Robergs, Robert A

    2011-11-01

    Glycerol has been used as a means to legitimately hyperhydrate the body in an attempt to offset the deleterious effects of dehydration. It has the potential to mask blood doping practices and as a result has been added to the WADA prohibited substance list. The purpose of this study was to identify the plasma glycerol concentration coinciding with urinary glycerol excretion. Twelve healthy, trained male subjects completed five separate trials under resting conditions. For each trial, subjects consumed a different glycerol dose (0.025, 0.05, 0.10, 0.15, or 0.20 g glycerol/kg LBM) of a 5% glycerol solution in order to determine at what plasma glycerol concentration an increase in urine glycerol concentration becomes apparent. Based on regression analysis, plasma glycerol concentrations > 0.327 ± 0.190 mmol/L and a glycerol dose > 0.032 ± 0.010 g glycerol/kg LBM would be associated with urinary glycerol excretion. There were significant linear relationships between peak plasma glycerol concentration and time to reach peak plasma glycerol concentration to the ingested glycerol doses. Our findings illustrate the importance of considering the effect of urinary glycerol excretion on legitimate hyperhydration regimens as well as suggesting that it is possible to detect surreptitious use of glycerol as a masking agent through urinary analysis. PMID:22080901

  3. Comparative Metabolism Studies of Hexabromocyclododecane (HBCD) Diastereomers in Male Rats Following a Single Oral Dose.

    PubMed

    Hakk, Heldur

    2016-01-01

    Male Sprague-Dawley rats were dosed orally with 3 mg/kg of one of three hexabromocyclododecane (HBCD) diastereomers. Each diastereomer was well absorbed (73-83%), and distributed preferentially to lipophilic tissues. Feces were the major route of excretion; cumulatively accounting for 42% of dose for α-HBCD, 59% for ß-HBCD, and 53% for γ-HBCD. Urine was also an important route of HBCD excretion, accounting for 13% of dose for α-HBCD, 30% for ß-HBCD, and 21% for γ-HBCD. Total metabolism of HBCD diastereomers followed the rank order ß > γ > α, and was >65% of that administered. The metabolites formed were distinct in male rats: α-HBCD did not debrominate or stereoisomerize, but formed two hydroxylated metabolites; ß- and γ-HBCD were both extensively metabolized via pathways of stereoisomerization, oxidation, dehydrogenation, reductive debromination, and ring opening. ß-HBCD was biotransformed to two mercapturic acid pathway metabolites. The metabolites of ß- and γ-HBCD were largely distinct, and could possibly be used as markers of exposure. These isomer-specific data suggest that α-HBCD would be the most dominant HBCD diastereomer in biological tissues because it was metabolized to the lowest degree and also accumulated from the stereoisomerization of the β- and γ- diastereomers. PMID:26629593

  4. Studies on the excretion of ascorbic acid 2-sulfate and total vitamin C into human urine after oral administration of ascorbic acid 2-sulfate.

    PubMed

    Tsujimura, M; Fukuda, T; Kasai, T

    1982-10-01

    The excretion of AsS and total vitamin C into urine after oral administration of AsS to humans was investigated. When 10 mmol of AsS was administered to the subjects, the excretion of AsS into urine continued for 60 hr in males and 48 hr in females. The average amount excreted per hour was less than 5 mg. These results differed from those for AsA and DAsA orally administered to humans. The determination of vitamin C after oral administration of AsS to the subjects consisting of ten males and six females showed no vitamin C effect in humans, similarly to the case with the guinea pig and the rhesus monkey. PMID:7161646

  5. Metabolism and excretion of the once-daily human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase.

    PubMed

    Malm-Erjefält, Monika; Bjørnsdottir, Inga; Vanggaard, Jan; Helleberg, Hans; Larsen, Uffe; Oosterhuis, Berend; van Lier, Jan Jaap; Zdravkovic, Milan; Olsen, Anette K

    2010-11-01

    Liraglutide is a novel once-daily human glucagon-like peptide (GLP)-1 analog in clinical use for the treatment of type 2 diabetes. To study metabolism and excretion of [(3)H]liraglutide, a single subcutaneous dose of 0.75 mg/14.2 MBq was given to healthy males. The recovered radioactivity in blood, urine, and feces was measured, and metabolites were profiled. In addition, [(3)H]liraglutide and [(3)H]GLP-1(7-37) were incubated in vitro with dipeptidyl peptidase-IV (DPP-IV) and neutral endopeptidase (NEP) to compare the metabolite profiles and characterize the degradation products of liraglutide. The exposure of radioactivity in plasma (area under the concentration-time curve from 2 to 24 h) was represented by liraglutide (≥89%) and two minor metabolites (totaling ≤11%). Similarly to GLP-1, liraglutide was cleaved in vitro by DPP-IV in the Ala8-Glu9 position of the N terminus and degraded by NEP into several metabolites. The chromatographic retention time of DPP-IV-truncated liraglutide correlated well with the primary human plasma metabolite [GLP-1(9-37)], and some of the NEP degradation products eluted very close to both plasma metabolites. Three minor metabolites totaling 6 and 5% of the administered radioactivity were excreted in urine and feces, respectively, but no liraglutide was detected. In conclusion, liraglutide is metabolized in vitro by DPP-IV and NEP in a manner similar to that of native GLP-1, although at a much slower rate. The metabolite profiles suggest that both DPP-IV and NEP are also involved in the in vivo degradation of liraglutide. The lack of intact liraglutide excreted in urine and feces and the low levels of metabolites in plasma indicate that liraglutide is completely degraded within the body. PMID:20709939

  6. Urinary iron excretion induced by intravenous infusion of deferoxamine in beta-thalassemia homozygous patients.

    PubMed

    Boturao-Neto, E; Marcopito, L F; Zago, M A

    2002-11-01

    The purpose of the present study was to identify noninvasive methods to evaluate the severity of iron overload in transfusion-dependent beta-thalassemia and the efficiency of intensive intravenous therapy as an additional tool for the treatment of iron-overloaded patients. Iron overload was evaluated for 26 beta-thalassemia homozygous patients, and 14 of them were submitted to intensive chelation therapy with high doses of intravenous deferoxamine (DF). Patients were classified into six groups of increasing clinical severity and were divided into compliant and non-compliant patients depending on their adherence to chronic chelation treatment. Several methods were used as indicators of iron overload. Total gain of transfusion iron, plasma ferritin, and urinary iron excretion in response to 20 to 60 mg/day subcutaneous DF for 8 to 12 h daily are useful to identify iron overload; however, urinary iron excretion in response to 9 g intravenous DF over 24 h and the increase of urinary iron excretion induced by high doses of the chelator are more reliable to identify different degrees of iron overload because of their correlation with the clinical grades of secondary hemochromatosis and the significant differences observed between the groups of compliant and non-compliant patients. Finally, the use of 3-9 g intravenous DF for 6-12 days led to a urinary iron excretion corresponding to 4.1 to 22.4% of the annual transfusion iron gain. Therefore, continuous intravenous DF at high doses may be an additional treatment for these patients, as a complement to the regular subcutaneous infusion at home, but requires individual planning and close monitoring of adverse reactions. PMID:12426631

  7. Absorption, Metabolism, and Excretion by Freely Moving Rats of 3,4-DHPEA-EDA and Related Polyphenols from Olive Fruits (Olea europaea).

    PubMed

    Kano, Shunsuke; Komada, Haruna; Yonekura, Lina; Sato, Akihiko; Nishiwaki, Hisashi; Tamura, Hirotoshi

    2016-01-01

    Absorption, metabolism, and excretion of 3,4-DHPEA-EDA, oleuropein, and hydroxytyrosol isolated from olive fruits were newly evaluated after oral and intravenous administration in freely moving rats cannulated in the portal vein, jugular vein, and bile duct. Orally administered 3,4-DHPEA-EDA, an important bioactive compound in olive pomace, was readily absorbed and metabolized to hydroxytyrosol, homovanillic acid, and homovanillyl alcohol, as shown by dose-normalized 4 h area under the curve (AUC0→4 h/Dose) values of 27.7, 4.5, and 4.2 μM·min·kg/μmol, respectively, in portal plasma after oral administration. The parent compound 3,4-DHPEA-EDA was not observed in the portal plasma, urine, and bile after oral and intravenous administration. Additionally, hydroxytyrosol, homovanillic acid, and homovanillyl alcohol in the portal plasma after oral administration of hydroxytyrosol showed 51.1, 22.8, and 7.1 μM·min·kg/μmol AUC0→4 h/Dose, respectively. When oleuropein, a polar glucoside, was injected orally, oleuropein in the portal plasma showed 0.9 μM·min·kg/μmol AUC0→4 h/Dose. However, homovanillic acid was detected from oleuropein in only a small amount in the portal plasma. Moreover, the bioavailability of hydroxytyrosol and oleuropein for 4 hours was 13.1% and 0.5%, respectively. Because the amount of 3,4-DHPEA-EDA in olive fruits is about 2-3 times greater than that of hydroxytyrosol, the metabolites of 3,4-DHPEA-EDA will influence biological activities. PMID:26904279

  8. Absorption, Metabolism, and Excretion by Freely Moving Rats of 3,4-DHPEA-EDA and Related Polyphenols from Olive Fruits (Olea europaea)

    PubMed Central

    Kano, Shunsuke; Komada, Haruna; Yonekura, Lina; Sato, Akihiko; Nishiwaki, Hisashi; Tamura, Hirotoshi

    2016-01-01

    Absorption, metabolism, and excretion of 3,4-DHPEA-EDA, oleuropein, and hydroxytyrosol isolated from olive fruits were newly evaluated after oral and intravenous administration in freely moving rats cannulated in the portal vein, jugular vein, and bile duct. Orally administered 3,4-DHPEA-EDA, an important bioactive compound in olive pomace, was readily absorbed and metabolized to hydroxytyrosol, homovanillic acid, and homovanillyl alcohol, as shown by dose-normalized 4 h area under the curve (AUC0→4 h/Dose) values of 27.7, 4.5, and 4.2 μM·min·kg/μmol, respectively, in portal plasma after oral administration. The parent compound 3,4-DHPEA-EDA was not observed in the portal plasma, urine, and bile after oral and intravenous administration. Additionally, hydroxytyrosol, homovanillic acid, and homovanillyl alcohol in the portal plasma after oral administration of hydroxytyrosol showed 51.1, 22.8, and 7.1 μM·min·kg/μmol AUC0→4 h/Dose, respectively. When oleuropein, a polar glucoside, was injected orally, oleuropein in the portal plasma showed 0.9 μM·min·kg/μmol AUC0→4 h/Dose. However, homovanillic acid was detected from oleuropein in only a small amount in the portal plasma. Moreover, the bioavailability of hydroxytyrosol and oleuropein for 4 hours was 13.1% and 0.5%, respectively. Because the amount of 3,4-DHPEA-EDA in olive fruits is about 2-3 times greater than that of hydroxytyrosol, the metabolites of 3,4-DHPEA-EDA will influence biological activities. PMID:26904279

  9. 16 CFR 1000.2 - Laws administered.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 16 Commercial Practices 2 2012-01-01 2012-01-01 false Laws administered. 1000.2 Section 1000.2 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION GENERAL COMMISSION ORGANIZATION AND FUNCTIONS § 1000.2 Laws administered. The Commission administers five acts: (a) The Consumer Product Safety Act...

  10. 16 CFR 1000.2 - Laws administered.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 16 Commercial Practices 2 2013-01-01 2013-01-01 false Laws administered. 1000.2 Section 1000.2 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION GENERAL COMMISSION ORGANIZATION AND FUNCTIONS § 1000.2 Laws administered. The Commission administers five acts: (a) The Consumer Product Safety Act...

  11. 16 CFR 1000.2 - Laws administered.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 16 Commercial Practices 2 2011-01-01 2011-01-01 false Laws administered. 1000.2 Section 1000.2 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION GENERAL COMMISSION ORGANIZATION AND FUNCTIONS § 1000.2 Laws administered. The Commission administers five acts: (a) The Consumer Product Safety Act...

  12. 16 CFR 1000.2 - Laws administered.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 16 Commercial Practices 2 2014-01-01 2014-01-01 false Laws administered. 1000.2 Section 1000.2 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION GENERAL COMMISSION ORGANIZATION AND FUNCTIONS § 1000.2 Laws administered. The Commission administers five acts: (a) The Consumer Product Safety Act...

  13. 16 CFR 1000.2 - Laws administered.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Laws administered. 1000.2 Section 1000.2 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION GENERAL COMMISSION ORGANIZATION AND FUNCTIONS § 1000.2 Laws administered. The Commission administers five acts: (a) The Consumer Product Safety Act...

  14. Ammonia excretion in aquatic and terrestrial crabs.

    PubMed

    Weihrauch, Dirk; Morris, Steve; Towle, David W

    2004-12-01

    The excretory transport of toxic ammonia across epithelia is not fully understood. This review presents data combined with models of ammonia excretion derived from studies on decapod crabs, with a view to providing new impetus to investigation of this essential issue. The majority of crabs preserve ammonotely regardless of their habitat, which varies from extreme hypersaline to freshwater aquatic environments, and ranges from transient air exposure to obligate air breathing. Important components in the excretory process are the Na+/K+(NH4+)-ATPase and other membrane-bound transport proteins identified in many species, an exocytotic ammonia excretion mechanism thought to function in gills of aquatic crabs such as Carcinus maenas, and gaseous ammonia release found in terrestrial crabs, such as Geograpsus grayi and Ocypode quadrata. In addition, this review presents evidence for a crustacean Rhesus-like protein that shows high homology to the human Rhesus-like ammonia transporter both in its amino acid sequence and in its predicted secondary structure. PMID:15579545

  15. Naloxone increases water and electrolyte excretion after water loading in patients with cirrhosis and ascites.

    PubMed

    Leehey, D J; Gollapudi, P; Deakin, A; Reid, R W

    1991-11-01

    Endogenous opioids may be involved in the pathogenesis of ascites and edema in patients with liver cirrhosis. We administered the opioid antagonist naloxone (5 mg bolus followed by a 0.06 mg/min infusion) to eight male patients with alcoholic cirrhosis and ascites and to five healthy age- and sex-matched control subjects and determined the effects of naloxone on water and electrolyte excretion after a nonsustained water load (20 ml/kg). In comparison with saline vehicle infusion carried out in the same subjects, naloxone administration resulted in a 50% increase in urine output and creatinine clearance and twofold increases in sodium and potassium excretion in patients with cirrhosis. Fractional sodium and potassium excretion, minimal urinary osmolality, plasma vasopressin and aldosterone levels, arterial blood pressure, and heart rate were not affected by naloxone treatment. The diuretic effect of naloxone was not observed in control subjects. Plasma naloxone levels were about six times higher in patients with cirrhosis than in control subjects (probably because of impaired metabolism of the drug) but only a weak correlation was found between drug levels and the degree of diuresis observed. The diuretic effect of naloxone may be related to an increase in glomerular filtration rate, possibly in conjunction with altered tubular reabsorption. PMID:1940589

  16. Modeling single cell antibody excretion on a biosensor.

    PubMed

    Stojanović, Ivan; Baumgartner, Wolfgang; van der Velden, Thomas J G; Terstappen, Leon W M M; Schasfoort, Richard B M

    2016-07-01

    We simulated, using Comsol Multiphysics, the excretion of antibodies by single hybridoma cells and their subsequent binding on a surface plasmon resonance imaging (SPRi) sensor. The purpose was to confirm that SPRi is suitable to accurately quantify antibody (anti-EpCAM) excretion. The model showed that antibody loss by diffusion away from the sensor was less than 1%. Unexpectedly, more than 99% of the excreted antibodies were captured on the sensor. These data prove the remarkable phenomenon that the SPRi output of cellular antibody excretion and its subsequent binding, performed under the conditions described here, is directly usable for quantification of single cell antibody production rates. PMID:27040182

  17. Biliary excretion of pravastatin and taurocholate in rats with bile salt export pump (Bsep) impairment.

    PubMed

    Cheng, Yaofeng; Freeden, Chris; Zhang, Yueping; Abraham, Pamela; Shen, Hong; Wescott, Debra; Humphreys, W Griffith; Gan, Jinping; Lai, Yurong

    2016-07-01

    The bile salt export pump (BSEP) is expressed on the canalicular membrane of hepatocytes regulating liver bile salt excretion, and impairment of BSEP function may lead to cholestasis in humans. This study explored drug biliary excretion, as well as serum chemistry, individual bile acid concentrations and liver transporter expressions, in the SAGE Bsep knockout (KO) rat model. It was observed that the Bsep protein in KO rats was decreased to 15% of that in the wild type (WT), as quantified using LC-MS/MS. While the levels of Ntcp and Mrp2 were not significantly altered, Mrp3 expression increased and Oatp1a1 decreased in KO animals. Compared with the WT rats, the KO rats had similar serum chemistry and showed normal liver transaminases. Although the total plasma bile salts and bile flow were not significantly changed in Bsep KO rats, individual bile acids in plasma and liver demonstrated variable changes, indicating the impact of Bsep KO. Following an intravenous dose of deuterium labeled taurocholic acid (D4-TCA, 2 mg/kg), the D4-TCA plasma exposure was higher and bile excretion was delayed by approximately 0.5 h in the KO rats. No differences were observed for the pravastatin plasma concentration-time profile or the biliary excretion after intravenous administration (1 mg/kg). Collectively, the results revealed that these rats have significantly lower Bsep expression, therefore affecting the biliary excretion of endogenous bile acids and Bsep substrates. However, these rats are able to maintain a relatively normal liver function through the remaining Bsep protein and via the regulation of other transporters. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27059119

  18. Excretion of ciprofloxacin into the large bowel of the rabbit.

    PubMed Central

    Ramon, J; Dautrey, S; Farinoti, R; Carbon, C; Rubinstein, E

    1996-01-01

    The intestinal elimination of ciprofloxacin in the large bowel was studied in a rabbit model. Segments from the cecum, colon, and sigmoid colon along with their intact blood vessels were isolated and perfused, and their contents were collected over a 90-min period following the administration of a single parenteral dose of 27 mg of ciprofloxacin per kg of body weight. The elimination rates of ciprofloxacin were 0.126 +/- 0.084 micrograms.min-1.cm-2 in the cecum and 0.264 +/- 0.126, 0.11 +/- 0.07, and 0.21 +/- 0.141 micrograms.min-1.cm-2 in the proximal colon, distal colon, and sigmoid colon, respectively. The calculated fraction of ciprofloxacin eliminated in the large bowel was 3% of the parenteral dose administered. The elimination pattern of ciprofloxacin in the large bowel may explain the unusual activity of this fluoroquinolone in modifying the colonic flora. PMID:8787870

  19. [Renal excretion of dimethylphosphate and its thio-derivatives following application of dimethoate, bromophos, naled or trichlorfon to rats].

    PubMed

    Riemer, F; Dahlenburg, R; Grisk, A

    1985-01-01

    Dimethoate, bromophos, naled or trichlorophon were applied i.p. or p.o. to rats in 3 doses each differing by the factor 10. In the urine of 24 h gas chromatographic determination of dimethylphosphate (DM), O.O-dimethylthiophosphate (TP), and/or O.O-dimethyldithiophosphate (DT) were carried out. After i.p. application of dimethoate the excretion rate of DT calculated from the dates found with the lowest dosage differed significantly from those found with the two other doses (t-test; p = 0.01). The excretion rates of DM and TP, in the same way, or those of DM, TP, and DT after oral intake of dimethoate did not show any significant differences. The excretion rates of TP after bromophos and of DM after naled or trichlorophon did not differ significantly after the same way of application. The findings make evident that under the given test conditions the excretion rate of DM, TP, or DT is practically independent on the dose. PMID:4000249

  20. Saliva versus plasma pharmacokinetics: theory and application of a salivary excretion classification system.

    PubMed

    Idkaidek, Nasir; Arafat, Tawfiq

    2012-08-01

    The aims of this work were to study pharmacokinetics of randomly selected drugs in plasma and saliva samples in healthy human volunteers, and to introduce a Salivary Excretion Classification System. Saliva and plasma samples were collected for 3-5 half-life values of sitagliptin, cinacalcet, metformin, montelukast, tolterodine, hydrochlorothiazide (HCT), lornoxicam, azithromycin, diacerhein, rosuvastatin, cloxacillin, losartan and tamsulosin after oral dosing. Saliva and plasma pharmacokinetic parameters were calculated by noncompartmental analysis using the Kinetica program. Effective intestinal permeability (Peff) values were estimated by the Nelder-Mead algorithm of the Parameter Estimation module using the SimCYP program. Peff values were optimized to predict the actual average plasma profile of each drug. All other physicochemical factors were kept constant during the minimization processes. Sitagliptin, cinacalcet, metformin, tolterodine, HCT, azithromycin, rosuvastatin and cloxacillin had salivary excretion with correlation coefficients of 0.59-0.99 between saliva and plasma concentrations. On the other hand, montelukast, lornoxicam, diacerhein, losartan and tamsulosin showed no salivary excretion. Estimated Peff ranged 0.16-44.16 × 10(-4) cm/s, while reported fraction unbound to plasma proteins (fu) ranged 0.01-0.99 for the drugs under investigation. Saliva/plasma concentrations ratios ranged 0.11-13.4, in agreement with drug protein binding and permeability. A Salivary Excretion Classification System (SECS) was suggested based on drug high (H)/low (L) permeability and high (H)/low (L) fraction unbound to plasma proteins, which classifies drugs into 4 classes. Drugs that fall into class I (H/H), II (L/H) or III (H/L) are subjected to salivary excretion, while those falling into class IV (L/L) are not. Additional data from literature was also analyzed, and all results were in agreement with the suggested SECS. Moreover, a polynomial relationship with

  1. Uptake and excretion of ( UC)methyl bromide as influenced by exposure concentration

    SciTech Connect

    Medinsky, M.A.; Dutcher, J.S.; Bond, J.A.; Henderson, R.F.; Mauderly, J.L.; Snipes, M.B.; Mewhinney, J.A.; Cheng, Y.S.; Birnbaum, L.S.

    1985-01-01

    Uptake of methyl bromide and pathways for excretion of UC were investigated in male Fischer-344 rats after nose-only inhalation of 50, 300, 5700, or 10,400 nmol (1.6 to 310 ppm) of ( UC)methyl bromide/liter of air for 6 hr. Fractional uptake of methyl bromide decreased at the highest concentrations, 5700 and 10,400 nmol/liter, with 37 and 27% of the inhaled methyl bromide absorbed, respectively, compared to 48% at the lower levels. Total methyl bromide absorbed was 9 or 40 mol/kg body wt after exposure to 50 or 300 nmol/liter, respectively. Elimination of UC was linearly related to the amount of methyl bromide absorbed as determined from urine, feces, expired CO2, and parent compound collected for 66 hr after the end of exposure. Exhaled UCO2 was the dominant route of excretion, with from 1.2 to 110 mol (50% of amount absorbed) exhaled, and was described by a two-component negative exponential function; 85% was exhaled with t1/2 of 4 hr, and the remaining 15% was exhaled with a t1/2 of 17 hr. The rate of exhalation of UCO2 was not affected by the amount of ( UC)methyl bromide absorbed. From 0.4 to 54 mol was excreted in urine (20% of amount absorbed). The half-time for excretion of UC in urine was approximately 10 hr, and the rate of excretion was not dependent on the amount of ( UC)methyl bromide absorbed. Little UC was exhaled as methyl bromide (<4% of the dose) or excreted in feces (<2%). At the end of 66 hr, 25% of the UC absorbed remained in the rats. Liver, kidneys, adrenals, lungs, thymus, and turbinates (maxilloturbinates, ethmoturbinates, and nasal epithelial membrane) contained the highest concentrations of UC. Results indicated that uptake of inhaled methyl bromide could be saturated. Any ( UC)methyl bromide equivalents absorbed, however, would be excreted by concentration-independent mechanisms. 20 references, 5 figures, 4 tables.

  2. Effects of combined treatment with diethyldithiocarbamate and diethylenetriaminepentaacetate on organ distribution and excretion of cadmium

    SciTech Connect

    Gale, G.R.; Atkins, L.M.; Walker, E.M. Jr.; Smith, A.B.

    1983-09-01

    Diethyldithiocarbamate (DDTC) and diethylenetriaminepentaacetate (DTPA) were assessed to determine if combination treatment with these two chelators of different chemical classes would enhance mobilization and excretion of metallothionein-bound cadmium (Cd) from selected organs of mice which had earlier received 0.03 mg of CdCl/sub 2/ . 2.5 H/sub 2/O along with 1.0 microCi of /sup 109/Cd. In addition to measuring individual organ radioactivity after seven and after 13 injections of each compound individually as well as in combination, whole body Cd burden was measured, and the routes and rates of Cd excretion were determined. When used alone, DDTC was effective in mobilizing Cd from kidney, liver, intestine, and spleen. The DTPA when used alone was not consistently effective in reducing Cd burdens in any of the organs assessed. Co-administration of DDTC and DTPA promoted an enhancement of Cd mobilization from liver, kidney, spleen, and intestine over that which was observed with DDTC alone. When DTPA was administered with DDTC, it did not prevent accumulation of Cd in lung and brain which was observed upon treatment with DDTC alone. Combined treatment did produce a more marked depletion of total body /sup 109/Cd burden than did the administration of DDTC alone. A more rapid rate of both fecal and urinary excretion of Cd was observed when the chelators were co-administered. It was concluded that at least an additive or possibly supraadditive effect may be obtained by combining a dithiocarbamate chelator with one of the aminocarboxylate class in total body Cd decorporation.

  3. Plasma disposition, milk excretion and parasitological efficacy of mebendazole in donkeys naturally infected by Cyathostominae.

    PubMed

    Gokbulut, Cengiz; Aksit, Dilek; Santoro, Mario; Roncoroni, Cristina; Mariani, Ugo; Buono, Francesco; Rufrano, Domenico; Fagiolo, Antonio; Veneziano, Vincenzo

    2016-02-15

    Mebendazole (MBZ) has been licensed for use in horses and donkeys, however there are no data available in the literature regarding its pharmacokinetic disposition and efficacy in donkeys. This study was designed to determine the plasma disposition, milk excretion and anthelmintic efficacy of MBZ in donkeys naturally infected by Cyathostominae. The animals were allocated to three groups, each of six donkeys. One group was untreated control (C-group) and the others were treated using a paste formulation of MBZ administered per os at the manufacturer's recommended horse dosage of 10 mg/kg body weight (MBZ 1) and at the double horse dosage 20 mg/kg body weight (MBZ 2). Blood and milk samples were collected at various times between 1h and 120 h post treatment and analyzed by high performance liquid chromatography with photodiode array detector. Individual FECs (Faecal Egg Counts) were performed on each animal before the treatment (day-3) and weekly from day 7 until day 56 post treatment using a modified McMaster technique. The plasma concentrations and systemic exposure of MBZ in donkeys were relatively lower compared with the other methylcarbamate benzimidazoles. Dose-dependent plasma dispositions of MBZ were observed at the increased dosage (10 mg/kg vs 20 mg/kg) in donkeys. MBZ was not detected in any milk samples at a dosage of 10 mg/kg. However, the parent drug reached 0.01 μg/ml peak milk concentration at 10.66 h and AUCmilk/AUCplasma value was 0.18 ± 0.02 at a dosage of 20 mg/kg bodyweight. This study indicated that per os administration of MBZ has a minimal disposition rate into the milk and may be used in lactating donkeys with zero milk-withdrawal period. The results of FECRT for both MBZ dosages were efficient (>95% efficacy) until day 28. This trial demonstrates that MBZ oral paste at horse dosage (10 mg/kg B.W.) was effective and safety for the treatment of Cyathostominae in donkeys. Therefore, similar dosage regimens of MBZ could be used for horses and

  4. [Stimulation of the fecal excretion of polychlorinated biphenyls (KC-600) by diets containing rice bran fiber and cholestyramine].

    PubMed

    Takenaka, S; Morita, K; Takahashi, K

    1991-05-01

    Among the eight kinds of dietary fiber tested, rice bran fiber (RBF) mostly bound Kanechlor 600 (PCB) in vitro. The PCB bound to dietary fiber was in proportion to the lignin content in dietary fiber. We investigated whether RBF, lignin, cholestyramine and their combination stimulate the fecal excretion of PCB in rats. In the group fed a diet containing 10% (w/w) RBF, fecal excretion of PCB was stimulated. In the group fed a diet containing 10% (w/w) RBF and 5% (w/w) cholestyramine, more PCB was excreted in the feces. However, the group fed a diet containing 10% (w/w) RBF and 5% (w/w) lignin excreted the same amount of PCB as the group fed a diet containing 10% (w/w) RBF. The total PCB excreted into the feces for 21 days in the groups fed 10% (w/w) RBF, 10% (w/w) RBF and 5% (w/w) lignin, 5% (w/w) cholestyramine and 10% (w/w) RBF and 5% (w/w) cholestyramine diet was 3.4, 3.8, 2.3 and 5.7 times, respectively, that of the control. The stool transit time of rats fed 10% (w/w) RBF and 5% (w/w) cholestyramine diet was one hour faster than that of rats fed a 5% (w/w) cholestyramine diet. Therefore, we concluded that RBF has the greatest effect when administered in combination with cholestyramine on the fecal excretion of PCB. PMID:1655599

  5. Urinary excretion of meperidine and its metabolites.

    PubMed

    Yeh, S Y; Krebs, H A; Changchit, A

    1981-08-01

    The urine of male and female mice, rats, guinea pigs, rabbits, cats, and dogs, given meperidine hydrochloride, 20--40 mg/kg ip, was analyzed by GLC for meperidine, normeperidine, p-hydroxymeperidine, and total (free and conjugated) meperidinic and normeperidinic acids. More than 90% of the excreted drugs was found in the 24-hr urine. Meperidine was observed in the urine of mice, rats, guinea pigs, and cats, but only a trace amount was observed in the urine of rabbits and dogs. Normeperidine, p-hydroxymeperidine (except in the mice), and total meperidinic and normeperidinic acids were observed in all species. All of the species studied have the capacity to N-demethylate meperidine to normeperidine and to hydrolyze meperidine and normeperidine to their respective acids. The male has a higher N-demethylating activity that the female with the exception of mice. Ester hydrolysis is a major metabolic pathway for meperidine metabolism. PMID:7310653

  6. Urinary excretion of enzymes following repeated parenteral administration of cadmium to rats

    SciTech Connect

    Bonner, F.W.; King, L.J.; Parke, D.V.

    1980-06-01

    The effect of daily parenteral administration of cadmium (0.75, 1.5, and 3.0 mg/kg) on the urinary excretion of enzymes has been studied in the young male rat. Aspartate aminotransferase, alkaline phosphatase, ..gamma..-glutamyl transpeptidase, and leucine aminopeptidase all showed an initial significant increase around the second day of dosage, the intensity of which was dose related. A second phase of enzymuria occurred later, the onset of which was dose related. High-dose-group animals (3.0 mg/kg) exhibited this increase around Day 15, while the median (1.5 mg/kg) and low- (0.75 mg/kg)dose-group animals developed enzymuria around Days 21 and 38, respectively. This second phase of elevated enzyme levels in the urine was persistent, and is believed to represent the development of renal damage.

  7. Stereoselectivity in the urinary excretion of the mercapturates of (R-) and (S-) alpha-bromoisovalerylurea in man.

    PubMed Central

    te Koppele, J M; Schipper, C; Breimer, D D; Mulder, G J

    1989-01-01

    1. alpha-Bromoisovalerylurea (BIU) is a racemic drug that is metabolized by glutathione conjugation. The urinary excretion of the separate diastereomeric mercapturates formed from (S)- and (R)-BIU in healthy young human volunteers was investigated. 2. A pronounced stereoselectivity was observed: the mercapturate formed from R-BIU was excreted with a t1/2 of 1.5 +/- 0.4 h, while that from S-BIU showed a t1/2 of 3.1 +/- 1.3 h. Moreover, 22.5 +/- 4.3 and 5.7 +/- 1.6% of the dose, respectively, was excreted as each mercapturate diastereomer in 24 h. 3. This is the first example of stereoselectivity in the elimination of a substrate for glutathione conjugation in man. PMID:2775620

  8. Body Iron Excretion by Healthy Men and Women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Iron excretion measured by isotope dilution has been a primary basis for factorial derivation of recommendations for iron intake, but results have been available for men only. Objective: The objective of this study was to reproduce iron excretion measurements in healthy men and extend th...

  9. INTESTINAL EXCRETION OF ENDOGENOUS ZINC IN GUATEMALAN SCHOOL CHILDREN

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: The intestine is the major route of excretion of endogenous zinc and has a key role in maintaining zinc homeostasis. Phytate has been reported to increase these losses. Objective: To determine the rate of excretion of endogenous zinc in school-aged children in a poor rural community for ...

  10. Effect of dietary supplementation of essential oils mixture on performance, eggshell quality, hatchability, and mineral excretion in quail breeders.

    PubMed

    Olgun, Osman; Yıldız, Alp Önder

    2014-12-01

    The main aim of this study was to investigate the effect of six different levels (0, 50, 100, 200, 400, and 600 mg/kg) of phytogenic feed additive containing a mixture essential oils from thyme, black cumin, fennel, anise and rosemary on performance, eggshell quality, reproductive traits, and mineral excretion in quail breeders. In this trial, a total of 60 male and 120 female quails, 91 days old, were randomly distributed in six experimental groups. During the 60-day experiment period, birds were fed with six treatment diets. Performances, eggshell qualities, hatchability, and mineral excretion data were evaluated at the end of the experiment. Results showed that the different dietary levels of essential oil mixture had no significant effect on performance parameters, damaged eggs, eggshell weight, fertility, hatchability of fertile eggs, hatchability of set eggs, and lead and boron excretion. On the other hand, 50 mg/kg supplementation of essential oil mixture (EOM) significantly improved egg-breaking strength and eggshell thickness, and ash, calcium, phosphorus, magnesium, manganese, zinc, and cadmium excretion was significantly depressed in quail breeders supplemented with the two higher doses (400 or 600 mg/kg) of EOM. These results concluded that supplementing diets with EOM improved egg-breaking strength and decreased excretion of minerals in breeder quails. PMID:25012208

  11. Excretion of N-mononitrosopiperazine after low level exposure to piperazine in air: effects of dietary nitrate and ascorbate

    SciTech Connect

    Bellander, T.; Osterdahl, B.G.; Hagmar, L.

    1988-04-01

    The secondary amine piperazine may be nitrosated in vivo, following oral intake or occupational exposure by inhalation. The suspected carcinogen N-mononitrosopiperazine could be formed in the human stomach, and in part excreted in the urine. In this study, 0.4 microgram N-mononitrosopiperazine, determined by gas chromatography-Thermal Energy Analysis, was observed in the urine in one of four volunteers, at an experimental exposure by inhalation of 0.3 mg piperazine/m3. The intake of spinach and beetroot caused an increased nitrosation of piperazine, and up to 1.7 microgram N-mononitrosopiperazine was excreted in the urine in the four individuals. This excretion indicates that about 5% of the absorbed piperazine dose was converted to N-mononitrosopiperazine. With the same nitrate-rich diet, but with the addition of citrus fruits and fresh vegetables, the highest excretion was 0.6 microgram N-mononitrosopiperazine. The excretion was significantly correlated with the ratio between the maximum level of nitrite in saliva and the ascorbate level in plasma. There was also a significant interindividual variation. N,N'-Dinitrosopiperazine was not found in any sample of urine.

  12. Persistence of urinary excretion products of benzo(a)pyrene

    SciTech Connect

    Uziel, M.; Haglund, R.; White, D.A.

    1988-01-01

    Persistence of DNA-adducts has been observed in a variety of experimental circumstances and has been suggested as one potential mechanism for explaining the long-term delay before expression of proliferative disease. In this concept, a stable DNA-adduct, which is a remnant of a prior exposure in a nondividing cell, would not express the genotoxic effect until the cells were stimulated to divide, and thus explain the long-term delay in expression of cancer. An alternative view of the observation of persistent DNA-adducts, described in this communication, is the continuing replenishment of DNA adducts by formation and turnover of these adducts from exposure to a constant supply of the ultimate carcinogenic species derived from a prior exposure. It is of interest to note that virtually all experiments where ''persistent'' adducts have been observed have been high dose exposures. During the course of experiments designed to develop improved methods for detection of DNA adducts and related derivatives derived from polynuclear aromatic hydrocarbons (PAH), we observed that there was a continuous excretion of urinary derivatives of the injected benzo(a)pyrene (BaP) beyond the initial burst of detoxification. This report describes the time dependent distribution of those derivatives in blood, urine, feces, and at the site of injection. 11 refs., 5 figs., 4 tabs.

  13. Excretion of Transmissible Spongiform Encephalopathy Infectivity in Urine

    PubMed Central

    Gregori, Luisa; Kovacs, Gabor G.; Alexeeva, Irina; Budka, Herbert

    2008-01-01

    The route of transmission of most naturally acquired transmissible spongiform encephalopathy (TSE) infections remains speculative. To investigate urine as a potential source of TSE exposure, we used a sensitive method for detection and quantitation of TSE infectivity. Pooled urine collected from 22 hamsters showing clinical signs of 263K scrapie contained 3.8 ± 0.9 infectious doses/mL of infectivity. Titration of homogenates of kidneys and urinary bladders from the same animals gave concentrations 20,000-fold greater. Histologic and immunohistochemical examination of these same tissues showed no indications of inflammatory or other pathologic changes except for occasional deposits of disease-associated prion protein in kidneys. Although the source of TSE infectivity in urine remains unresolved, these results establish that TSE infectivity is excreted in urine and may thereby play a role in the horizontal transmission of natural TSEs. The results also indicate potential risk for TSE transmission from human urine–derived hormones and other medicines. PMID:18760007

  14. Urinary excretion of polyethylene glycol 3350 and sulfate after gut lavage with a polyethylene glycol electrolyte lavage solution.

    PubMed

    Brady, C E; DiPalma, J A; Morawski, S G; Santa Ana, C A; Fordtran, J S

    1986-06-01

    Ingestion of an electrolyte lavage solution containing polyethylene glycol 3350 and sulfate is an effective method of cleansing the colon for diagnostic studies. Polyethylene glycol and sulfate are considered poorly absorbed from the gastrointestinal tract. Because of the quantities administered, concern exists about potential toxicity of absorption of even a small percentage, particularly for polyethylene glycol. We measured the urinary excretion of both polyethylene glycol and sulfate in normal subjects and inflammatory bowel patients. Absorption of polyethylene glycol can be assessed by measuring recovery in urine, as 85%-96% of an intravenous load is excreted in urine. Similarly, appreciable sulfate absorption would exceed renal tubular reabsorption and result in increased urinary excretion. Mean percent polyethylene glycol load recovered in urine was minimal and similar for normal (0.06%) and inflammatory bowel (0.09%) subjects. Urinary sulfate excretion after lavage was also similar for both groups and was not different from baseline. These results do not suggest the likelihood of toxicity due to polyethylene glycol 3350 or sulfate absorption during gut lavage with this solution. PMID:3699408

  15. Evaluation of exposure to phenol: absorption of phenol vapour in the lungs and through the skin and excretion of phenol in urine

    PubMed Central

    Piotrowski, Jerzy K.

    1971-01-01

    Piotrowski, J. K. (1971).Brit. J. industr. Med.,28, 172-178. Evaluation of exposure to phenol: absorption of phenol vapour in the lungs and through the skin and excretion of phenol in urine. Volunteers were exposed to phenol vapour (5 to 25 mg/m3) by inhalation and through the skin, respectively, and the excretion of phenol in urine was examined. The retention of vapour in the lungs decreased from about 80 to 70% in the course of exposure. The absorption of vapour through the whole of the skin was approximately proportional to the concentration of vapour used, the absorption rate being somewhat lower than in the lungs. Almost 100% of the phenol was excreted in the urine within one day. The rate of excretion of phenol in the urine may be used as an exposure test which permits the absorbed dose to be estimated with a precision of about ±2 mg. PMID:5572685

  16. 22 CFR 196.4 - Administering office.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Administering office. 196.4 Section 196.4 Foreign Relations DEPARTMENT OF STATE INTERNATIONAL COMMERCIAL ARBITRATION THOMAS R. PICKERING FOREIGN AFFAIRS/GRADUATE FOREIGN AFFAIRS FELLOWSHIP PROGRAM § 196.4 Administering office. The Department of...

  17. 16 CFR 0.4 - Laws administered.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Laws administered. 0.4 Section 0.4 Commercial Practices FEDERAL TRADE COMMISSION ORGANIZATION, PROCEDURES AND RULES OF PRACTICE ORGANIZATION § 0.4 Laws administered. The Commission exercises enforcement and administrative authority under the Federal Trade Commission Act (15 U.S.C....

  18. 16 CFR 0.4 - Laws administered.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 16 Commercial Practices 1 2011-01-01 2011-01-01 false Laws administered. 0.4 Section 0.4 Commercial Practices FEDERAL TRADE COMMISSION ORGANIZATION, PROCEDURES AND RULES OF PRACTICE ORGANIZATION § 0.4 Laws administered. The Commission exercises enforcement and administrative authority under the Federal Trade Commission Act (15 U.S.C....

  19. 7 CFR 247.3 - Administering agencies.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 4 2010-01-01 2010-01-01 false Administering agencies. 247.3 Section 247.3 Agriculture Regulations of the Department of Agriculture (Continued) FOOD AND NUTRITION SERVICE, DEPARTMENT OF AGRICULTURE CHILD NUTRITION PROGRAMS COMMODITY SUPPLEMENTAL FOOD PROGRAM § 247.3 Administering agencies....

  20. Relaxation processes in administered-rate pricing

    NASA Astrophysics Data System (ADS)

    Hawkins, Raymond J.; Arnold, Michael R.

    2000-10-01

    We show how the theory of anelasticity unifies the observed dynamics and proposed models of administered-rate products. This theory yields a straightforward approach to rate model construction that we illustrate by simulating the observed relaxation dynamics of two administered rate products. We also demonstrate how the use of this formalism leads to a natural definition of market friction.

  1. A novel CRTH2 antagonist: Single- and multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ACT-453859 in healthy subjects.

    PubMed

    Géhin, Martine; Strasser, Daniel S; Zisowsky, Jochen; Farine, Hervé; Groenen, Peter M A; Dingemanse, Jasper; Sidharta, Patricia N

    2015-07-01

    The chemoattractant receptor-homologous molecule expressed on T-helper 2 cells (CRTH2) is a G-protein-coupled receptor for prostaglandin D2 , a key mediator in inflammatory disorders. In this randomized, double-blind, placebo-controlled study we investigated the single- and multiple-dose tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) up to a dose of 800 mg once a day of ACT-453859, a potent and selective CRTH2 antagonist. ACT-453859 was moderately rapidly absorbed and followed a biphasic elimination pattern, with an elimination half-life between 11 and 20 hours. Steady-state conditions were reached after 1 day, and ACT-453859 did not accumulate. Urinary excretion of unchanged ACT-453859 did not exceed 1.4% of the administered dose. Administration of ACT-453859 resulted in a dose-dependent blockadeof CRTH2 on the surface of eosinophils. The maximum PD effect of ACT-453859 was reached about 2.0 hours after dosing, which corresponded to the highest concentration at which PD were assessed. At steady state, 100 and 800 mg ACT-453859 once a day resulted in blockade of CRTH2 over 24 hours. In this entry-into-humans study, ACT-453859 showed good tolerability at all doses and a PK and PD profile compatible with once-daily dosing. PMID:25655470

  2. Safety of florfenicol administered in feed to tilapia (Oreochromis sp.)

    USGS Publications Warehouse

    Gaikowski, Mark P.; Wolf, Jeffrey C.; Schleis, Susan M.; Tuomari, Darrell; Endris, Richard G.

    2013-01-01

    The safety of Aquaflor® (50% w/w florfenicol [FFC]) incorporated in feed then administered to tilapia for 20 days (2x the recommended duration) at 0, 15, 45, or 75 mg/kg body weight/day (0, 1, 3, or 5x the recommended dose of 15 mg FFC/kg BW/d) was investigated. Mortality, behavioral change, feed consumption, body size, and gross and microscopic lesions were determined. Estimated delivered doses were >96.9% of target. Three unscheduled mortalities occurred but were considered incidental since FFC-related findings were not identified. Feed consumption was only affected during the last 10 dosing days when the 45 and 75 mg/kg groups consumed only 62.5% and 55.3% of the feed offered, respectively. There were significant, dose-dependent reductions in body size in the FFC-dose groups relative to the controls. Treatment-related histopathological findings included increased severity of lamellar epithelial hyperplasia, increased incidence of lamellar adhesions, decreased incidence of lamellar telangiectasis in the gills, increased glycogen-type and lipid-type hepatocellular vacuolation in the liver, decreased lymphocytes, increased blast cells, and increased individual cell necrosis in the anterior kidney, and tubular epithelial degeneration and mineralization in the posterior kidney. These changes are likely to be of minimal clinical relevance, given the lack of mortality or morbidity observed. This study has shown that FFC, when administered in feed to tilapia at the recommended dose (15 mg FFC/kg BW/day) for 10 days would be well tolerated.

  3. Excretion of drugs in human breast milk

    SciTech Connect

    Welch, R.M.; Findlay, J.W.

    1981-01-01

    The present report briefly discusses some of the morphological, physiological, and compositional aspects of animal and human breast milk and how these characteristics might be important for the accumulation of drugs and foreign compounds. In addition, a study is described confirming the presence of caffeine, codeine, morphine, phenacetin, acetaminophen, and salicylic acid in the breast milk of a lactating mother following oral administration of a combination analgesic containing aspirin, phenacetin, caffeine, and codeine. Although the study is limited to one subject, it has provided critically needed data on the rates of appearance in, and elimination of these drugs from, breast milk. A similar amount of information is presented on phenacetin, also a component of the analgesic mixture, which has not been previously reported to enter human milk. The distribution of these drugs between the slightly more acidic breast milk and the relatively neutral plasma is consistent with their weakly basic, acidic, or relatively neutral properties. In general, the study shows that codeine and morphine milk concentrations are higher than, salicylic acid milk levels are much lower than, and phenacetin, caffeine, and acetaminophen milk concentrations are relatively similar to their respective plasma levels. It is projected, from estimated steady-state milk concentrations of the drugs and their metabolites studied, that very low percentages of the therapeutic dosages (less than 0.7%) would be excreted in mother's milk, too low an amount to be clinically significant to the infant.

  4. Excretion of biliary compounds during intrauterine life

    PubMed Central

    Macias, Rocio IR; Marin, Jose JG; Serrano, Maria A

    2009-01-01

    In adults, the hepatobiliary system, together with the kidney, constitute the main routes for the elimination of several endogenous and xenobiotic compounds into bile and urine, respectively. However, during intrauterine life the biliary route of excretion for cholephilic compounds, such as bile acids and biliary pigments, is very poor. Although very early in pregnancy the fetal liver produces bile acids, bilirubin and biliverdin, these compounds cannot be efficiently eliminated by the fetal hepatobiliary system, owing to the immaturity of the excretory machinery in the fetal liver. Therefore, the potentially harmful accumulation of cholephilic compounds in the fetus is prevented by their elimination across the placenta. Owing to the presence of detoxifying enzymes and specific transport systems at different locations of the placental barrier, such as the endothelial cells of chorionic vessels and trophoblast cells, this organ plays an important role in the hepatobiliary-like function during intrauterine life. The relevance of this excretory function in normal fetal physiology is evident in situations where high concentrations of biliary compounds are accumulated in the mother. This may result in oxidative stress and apoptosis, mainly in the placenta and fetal liver, which might affect normal fetal development and challenge the fate of the pregnancy. The present article reviews current knowledge of the mechanisms underlying the hepatobiliary function of the fetal-placental unit and the repercussions of several pathological conditions on this tandem. PMID:19230042

  5. Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine.

    PubMed

    Zeng, Teng; Mitch, William A

    2016-06-01

    The H2-receptor antagonist, ranitidine, is among the most widely used pharmaceuticals to treat gastroesophageal reflux disease and peptic ulcers. While previous studies have demonstrated that amines can form N-nitrosamines when exposed to nitrite at stomach-relevant pH, N-nitrosamine formation from ranitidine, an amine-based pharmaceutical, has not been demonstrated under these conditions. In this work, we confirmed the production of N-nitrosodimethylamine (NDMA), a potent carcinogen, by nitrosation of ranitidine under stomach-relevant pH conditions in vitro We also evaluated the urinary NDMA excretion attributable to ingestion of clinically used ranitidine doses. Urine samples collected from five female and five male, healthy adult volunteers over 24-h periods before and after consumption of 150mg ranitidine were analyzed for residual ranitidine, ranitidine metabolites, NDMA, total N-nitrosamines and dimethylamine. Following ranitidine intake, the urinary NDMA excreted over 24h increased 400-folds from 110 to 47 600ng, while total N-nitrosamines increased 5-folds. NDMA excretion rates after ranitidine intake equaled or exceeded those observed previously in patients with schistosomiasis, a disease wherein N-nitrosamines are implicated as the etiological agents for bladder cancer. Due to metabolism within the body, urinary NDMA measurements represent a lower-bound estimate of systemic NDMA exposure. Our results suggest a need to evaluate the risks attributable to NDMA associated with chronic consumption of ranitidine, and to identify alternative treatments that minimize exposure to N-nitrosamines. PMID:26992900

  6. Turnover and urinary excretion of free and acetylated MS-222 rainbow trout, Salmo gairdneri

    USGS Publications Warehouse

    Hunn, J.B.; Schoettger, R.A.; Willford, W.A.

    1968-01-01

    Rainbow trout (Salmo gairdneri) anesthetized in 100 mg/liter of M.S. 222 at 12 C excreted the drug in free and acetylated forms via the urine during a 24-hr recovery period in freshwater. Of the M.S. 222 excreted, 77-96% was acetylated. Blood levels of free drug in anesthetized trout approximated 75% of the anesthetic concentration, but the amount of acetylated M.S. 222 was relatively insignificant. The blood and urine were cleared of the two fractions of M.S. 222 in 8 and 24 hr respectively. Low levels of aromatic amines of natural origin occurred in blood and urine and were subtracted from measurements of M.S. 222. Intraperitoneal injections of 10-100 mg/kg of M.S. 222 did not induce anesthesia; however, the 24-hr pattern of drug excretion was similar to that observed after anesthesia by immersion. Only 15-21 % of the injected dose was found in the urine, suggesting a second route of drug elimination.

  7. Cortisol-mediated synchronization of circadian rhythm in urinary potassium excretion

    NASA Technical Reports Server (NTRS)

    Moore-Ede, M. C.; Schmelzer, W. S.; Kass, D. A.; Herd, J. A.

    1977-01-01

    Conscious chair-acclimatized squirrel monkeys (Saimiri sciureus) studied with lights on (600 lx) from 0800 to 2000 hr daily (LD 12:12) display a prominent circadian rhythm in renal potassium excretion. The characteristics of this rhythm were reproduced in adrenalectomized monkeys by infusing 5 mg cortisol and 0.001 mg aldosterone, or 5 mg cortisol alone, between 0800 and 0900 kr daily. When the timing of cortisol administration (with or without aldosterone) was phase-delayed by 8 hr, the urinary potassium rhythm resynchronized by 80% of the cortisol phase shift, but only after a transient response lasting 3-4 days. With the same daily dose of adrenal steroids given as a continuous infusion throughout each 24 hr, urinary potassium excretion showed free-running oscillations no longer synchronized to the light-dark cycle. These results indicate that the circadian rhythm of plasma cortisol concentration acts as an internal mediator in the circadian timing system, synchronizing a potentially autonomous oscillation in renal potassium excretion to environmental time cues and to other circadian rhythms within the animal.

  8. Increased urinary excretion of toxic hydrazino metabolites of isoniazid by slow acetylators. Effect of a slow-release preparation of isoniazid.

    PubMed

    Peretti, E; Karlaganis, G; Lauterburg, B H

    1987-01-01

    To test the hypothesis that slow acetylators, who may have a greater risk of developing isoniazid hepatitis than rapid acetylators, are exposed to more acetylhydrazine and hydrazine, two toxic metabolites of isoniazid, the urinary excretion of hydrazino metabolites of isoniazid was measured following the ingestion of 300 mg isoniazid. Slow acetylators (n = 7) excreted significantly more isoniazid (32.4 vs 9.2% dose), acetylhydrazine (3.1 vs 1.6% dose), and hydrazine (1.0 vs 0.4% dose) in 24 h than rapid acetylators (n = 5), whereas the excretion of acetylisoniazid and diacetylhydrazine was significantly lower. As the acetylation (i.e. detoxification) of acetylhydrazine is inhibited in the presence of high concentrations of isoniazid, a study was also made of the effect of a slow-release preparation that results in lower plasma concentrations of isoniazid on the production of hydrazino metabolites. The ratio of acetylisoniazid to isoniazid in urine was significantly increased in slow acetylators from 0.84 to 1.02 following administration of the slow release preparation, indicating increased acetylation of isoniazid. However, the excretion of diacetylhydrazine relative to the excretion of acetylhydrazine and hydrazine did not change. It is concluded that exposure to toxic metabolites of isoniazid is increased in slow acetylators. Detoxification of the toxic metabolites was not enhanced by a slow-release preparation of isoniazid. PMID:3691615

  9. Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers

    NASA Astrophysics Data System (ADS)

    Singh, Ravi; Pantarotto, Davide; Lacerda, Lara; Pastorin, Giorgia; Klumpp, Cédric; Prato, Maurizio; Bianco, Alberto; Kostarelos, Kostas

    2006-02-01

    Carbon nanotubes (CNT) are intensively being developed for biomedical applications including drug and gene delivery. Although all possible clinical applications will require compatibility of CNT with the biological milieu, their in vivo capabilities and limitations have not yet been explored. In this work, water-soluble, single-walled CNT (SWNT) have been functionalized with the chelating molecule diethylentriaminepentaacetic (DTPA) and labeled with indium (111In) for imaging purposes. Intravenous (i.v.) administration of these functionalized SWNT (f-SWNT) followed by radioactivity tracing using gamma scintigraphy indicated that f-SWNT are not retained in any of the reticuloendothelial system organs (liver or spleen) and are rapidly cleared from systemic blood circulation through the renal excretion route. The observed rapid blood clearance and half-life (3 h) of f-SWNT has major implications for all potential clinical uses of CNT. Moreover, urine excretion studies using both f-SWNT and functionalized multiwalled CNT followed by electron microscopy analysis of urine samples revealed that both types of nanotubes were excreted as intact nanotubes. This work describes the pharmacokinetic parameters of i.v. administered functionalized CNT relevant for various therapeutic and diagnostic applications. nanomedicine | blood circulation half-life | drug delivery | pharmacokinetics | nanotoxicology

  10. Absolute bioavailability, pharmacokinetics, and urinary excretion of the novel antimigraine agent almotriptan in healthy male volunteers.

    PubMed

    Jansat, Josep M; Costa, Joan; Salvà, Pau; Fernandez, Francisco J; Martinez-Tobed, Antonio

    2002-12-01

    Absolute bioavailability, pharmacokinetics, and urinary excretion of almotriptan, a novel 5-HT(1B/1D) receptor agonist, were studied in 18 healthy males following single intravenous (i.v.) (3 mg), subcutaneous (s.c.) (6 mg), and oral (25 mg) doses. Volunteers received each dose in a randomized sequence separated by a 7-day washout. Blood and urine samples for pharmacokinetic evaluations were taken for up to 24 hours after dosing. The disposition kinetics of almotriptan after i.v. and s.c. administration showed biphasic decline described by a two-compartment model. The fastest disposition phase was well observed, although estimates of the rate constant showed high variability. After s.c. administration of almotriptan, the bioavailability was 100% with a time to maximum plasma concentration (tmax) of 5 to 15 minutes, whereas after oral administration, the bioavailability was about 70% with a tmax of 1.5 to 3.0 hours. No significant differences were observed between administration routes in the elimination half-life (t(1/2), obtaining mean values ranging from 3.4 to 3.6 hours. The volume of distribution, total clearance, and t(1/2) indicated that almotriptan was extensively distributed and rapidly cleared from the body irrespective of dose or route of administration. The primary route of elimination was renal clearance (approximately 50%-60% of total body clearance). About 65% of the i.v. and s.c. dose and 45% of the oral dose were excreted unchanged in urine in 24 hours, with nearly 90% of this in the first 12 hours. Renal clearance was approximately 2- to 3-fold that of the glomerular filtration rate in man, suggesting that almotriptan is eliminated in part by renal tubular secretion. PMID:12463724

  11. Occupational cadmium exposure and calcium excretion, bone density, and osteoporosis in men.

    PubMed

    Nawrot, Tim; Geusens, Piet; Nulens, Tom S; Nemery, Benoit

    2010-06-01

    Exposure to cadmium has been associated with osteoporosis and fracture risk in women and the elderly, but studies in middle-aged men are lacking. In 83 male (ex)workers (mean age 45 years; range 24 to 64 years) in a radiator factory using cadmium-containing solder, we investigated the association between urinary cadmium excretion (as an index of lifetime body burden); bone mineral density (BMD) in the distal forearm, hip, and lumbar spine (by dual-energy X-ray absorptiometry); and urinary calcium excretion. Geometric mean urinary cadmium concentration was 1.02 microg/g of creatinine (5th to 95th percentile 0.17 to 5.51 microg/g). BMD was negatively correlated with urinary exposure to cadmium. The partial correlation coefficients (r) adjusted for age, body-mass index, and current smoking were -0.30 (p = .008) for BMD in the forearm, -0.27 (p = .017) in the hip, and -0.17 (p = .15) in the spine. Urinary calcium correlated positively (r = 0.23, p = .044) with the urinary cadmium excretion. Adjusted for the same covariates, the risk of osteoporosis (defined as a T-score below -2.5 in at least one measured bone site) increased dose dependently. Compared with the lowest tertile of urinary cadmium, the risks were 4.8- and 9.9-fold higher in the middle and highest tertiles, respectively. Only four (5%) men had evidence of renal tubular dysfunction (beta(2)-microglobulin > 300 microg/g of creatinine). Even in the absence of renal tubular dysfunction, occupational exposure to cadmium is associated in men with lower BMD values, a higher risk of having osteoporosis, and a higher urinary calcium excretion, suggesting a direct osteotoxic effect of cadmium. PMID:20200937

  12. Comparison and Equating of Paper-Administered, Computer-Administered and Computerized Adaptive Tests of Achievement.

    ERIC Educational Resources Information Center

    Olsen, James B.; And Others

    Student achievement test scores were compared and equated, using three different testing methods: paper-administered, computer-administered, and computerized adaptive testing. The tests were developed from third and sixth grade mathematics item banks of the California Assessment Program. The paper and the computer-administered tests were identical…

  13. Human breast milk excretion of iodine-131 following diagnostic and therapeutic administration to a lactating patient with Graves' disease

    SciTech Connect

    Dydek, G.J.; Blue, P.W.

    1988-03-01

    Previous reports on the excretion of /sup 131/I into human breast milk have recommended discontinuance of breast feeding from 1 to 12 days following diagnostic tracer doses of /sup 131/I. Recent excretion models have calculated that breast feeding could safely resume 56 days following a 5 microCi (0.185 MBq) /sup 131/I maternal tracer dose. We studied a postpartum patient with Graves' disease following first an uptake dose of 8.6 microCi (0.317 MBq) and then for 38 days following a 9.6 mCi (355 MBq) therapy dose of Na/sup 131/I. We calculated from our data that although nursing could not be safely resumed for 46 days following the 8.6-microCi uptake dose, nursing could resume in this patient 8 days after a 100-nCi (3.7 KBq) dose. Extrapolating this data to impure /sup 123/I (p, 2n or p, 5n) we feel that standard 100-microCi (3.7 MBq) doses of either /sup 123/I preparation is not suitable if nursing is to be resumed.

  14. Pharmacokinetics, metabolism, and excretion of nefopam, a dual reuptake inhibitor in healthy male volunteers.

    PubMed

    Sanga, Madhu; Banach, John; Ledvina, Aaron; Modi, Nishit B; Mittur, Aravind

    2016-11-01

    1. The disposition of nefopam, a serotonin-norepinephrine reuptake inhibitor, was characterized in eight healthy male volunteers following a single oral dose of 75 mg [(14)C]-nefopam (100 μCi). Blood, urine, and feces were sampled for 168 h post-dose. 2. Mean (± SD) maximum blood and plasma radioactivity concentrations were 359 ± 34.2 and 638 ± 64.7 ngEq free base/g, respectively, at 2 h post-dose. Recovery of radioactive dose was complete (mean 92.6%); a mean of 79.3% and 13.4% of the dose was recovered in urine and feces, respectively. 3. Three main radioactive peaks were observed in plasma (metabolites M2 A-D, M61, and M63). Intact [(14)C]-nefopam was less than 5% of the total radioactivity in plasma. In urine, the major metabolites were M63, M2 A-D, and M51 which accounted for 22.9%, 9.8%, and 8.1% of the dose, respectively. An unknown entity, M55, was the major metabolite in feces (4.6% of dose). Excretion of unchanged [(14)C]-nefopam was minimal. PMID:26796604

  15. Dose esclation in radioimmunotherapy based on projected whole body dose

    SciTech Connect

    Wahl, R.L.; Kaminski, M.S.; Regan, D.

    1994-05-01

    A variety of approaches have been utilized in conducting phase I radioimmunotherapy dose-escalation trials. Escalation of dose has been based on graded increases in administered mCi; mCi/kg; or mCi/m2. It is also possible to escalate dose based on tracer-projected marrow, blood or whole body radiation dose. We describe our results in performing a dose-escalation trial in patients with non-Hodgkin lymphoma based on escalating administered whole-body radiation dose. The mCi dose administered was based on a patient-individualized tracer projected whole-body dose. 25 patients were entered on the study. RIT with 131 I anti-B-1 was administered to 19 patients. The administered dose was prescribed based on the projected whole body dose, determined from patient-individualized tracer studies performed prior to RIT. Whole body dose estimates were based on the assumption that the patient was an ellipsoid, with 131 antibody kinetics determined using a whole-body probe device acquiring daily conjugate views of 1 minute duration/view. Dose escalation levels proceeded with 10 cGy increments from 25 cGy whole-body and continues, now at 75 cGy. The correlation among potential methods of dose escalation and toxicity was assessed. Whole body radiation dose by probe was strongly correlated with the blood radiation dose determined from sequential blood sampling during tracer studies (r=.87). Blood radiation dose was very weakly correlated with mCi dose (r=.4) and mCi/kg (r=.45). Whole body radiation dose appeared less well-correlated with injected dose in mCi (r=.6), or mCi/kg (r=.64). Toxicity has been infrequent in these patients, but appears related to increasing whole body dose. Non-invasive determination of whole-body radiation dose by gamma probe represents a non-invasive method of estimating blood radiation dose, and thus of estimating bone marrow radiation dose.

  16. The metabolism of 4-trifluoromethoxyaniline and [13C]-4-trifluoromethoxyacetanilide in the rat: detection and identification of metabolites excreted in the urine by NMR and HPLC-NMR.

    PubMed

    Tugnait, M; Lenz, E M; Phillips, P; Hofmann, M; Spraul, M; Lindon, J C; Nicholson, J K; Wilson, I D

    2002-06-01

    A combination of 19F, 1H NMR and HPLC-NMR spectroscopic approaches have been used to quantify and identify the urinary-excreted metabolites of 4-trifluoromethoxyaniline (4-TFMeA) and its [13C]-labelled acetanilide following i.p. administration at 50 mg/kg to rats. The major metabolite excreted in the urine for both compounds was a sulphated ring-hydroxylated metabolite (either 2- or 3-trifluoromethyl-5-aminosulphate) which accounted for approximately 32.3% of the dose following the administration of 4-TFMeA and approximately 29.9% following dosing of the acetanilide. The trifluoromethoxy-substituent appeared to be metabolically stable, with no evidence of O-detrifluoromethylation. There was no evidence of the excretion of N-oxanilic acids in urine, of the type seen with 4-trifluoromethylaniline. PMID:12039629

  17. Ammonia excretion in mytilid mussels is facilitated by ciliary beating.

    PubMed

    Thomsen, J; Himmerkus, N; Holland, N; Sartoris, F J; Bleich, M; Tresguerres, M

    2016-08-01

    The excretion of nitrogenous waste products in the form of ammonia (NH3) and ammonium (NH4 (+)) is a fundamental process in aquatic organisms. For mytilid bivalves, little is known about the mechanisms and sites of excretion. This study investigated the localization and the mechanisms of ammonia excretion in mytilid mussels. An Rh protein was found to be abundantly expressed in the apical cell membrane of the plicate organ, which was previously described as a solely respiratory organ. The Rh protein was also expressed in the gill, although at significantly lower concentrations, but was not detectable in mussel kidney. Furthermore, NH3/NH4 (+) was not enriched in the urine, suggesting that kidneys are not involved in active NH3/NH4 (+) excretion. Exposure to elevated seawater pH of 8.5 transiently reduced NH3/NH4 (+) excretion rates, but they returned to control values following 24 h acclimation. These mussels had increased abundance of V-type H(+)-ATPase in the apical membranes of plicate organ cells; however, NH3/NH4 (+) excretion rates were not affected by the V-type H(+)-ATPase specific inhibitor concanamycin A (100 nmol l(-1)). In contrast, inhibition of ciliary beating with dopamine and increased seawater viscosity significantly reduced NH3 excretion rates under control pH (8.0). These results suggest that NH3/NH4 (+) excretion in mytilid mussels takes place by passive NH3 diffusion across respiratory epithelia via the Rh protein, facilitated by the water current produced for filter feeding, which prevents accumulation of NH3 in the boundary layer. This mechanism would be energy efficient for sessile organisms, as they already generate water currents for filter feeding. PMID:27489216

  18. Recovery of cholinesterase activity in mallard ducklings administered organophosphorus pesticides

    USGS Publications Warehouse

    Fleming, W.J.; Bradbury, S.P.

    1981-01-01

    Oral doses of the organophosphorus pesticides acephate, dicrotophos, fensulfothion, fonofos, malathion, and parathion were administered to mallard ducklings (Anas platyrhynchos), and brain and plasma cholinesterase (ChE) activities were determined for up to 77 d after dosing. In vivo recovery of brain ChE activity to within 2 standard deviations of the mean activity of undosed birds occurred within 8 d, after being depressed an average of 25-58% at 24 h after dosing. In vivo recovery of plasma ChE appeared as fast as or faster than that of brain, but the pattern of recovery was more erratic and therefore statistical comparison with brain ChE recovery was not attempted. In vitro tests indicated that the potential for dephosphorylation to contribute to in vivo recovery of inhibited brain ChE differed among chemical treatments. Some ducklings died as a result of organophosphate dosing. In an experiment in which ducklings within each treatment group received the same dose (mg/kg), the brain ChE activity in birds that died was less than that in birds that survived. Brain ChE activities in ducklings that died were significantly different among pesticide treatments: fensulfothion > parathion> acephate > malathion (p < 0.05).

  19. Absorption, Metabolism, Excretion, and the Contribution of Intestinal Metabolism to the Oral Disposition of [14C]Cobimetinib, a MEK Inhibitor, in Humans.

    PubMed

    Takahashi, Ryan H; Choo, Edna F; Ma, Shuguang; Wong, Susan; Halladay, Jason; Deng, Yuzhong; Rooney, Isabelle; Gates, Mary; Hop, Cornelis E C A; Khojasteh, S Cyrus; Dresser, Mark J; Musib, Luna

    2016-01-01

    The pharmacokinetics, metabolism, and excretion of cobimetinib, a MEK inhibitor, were characterized in healthy male subjects (n = 6) following a single 20 mg (200 μCi) oral dose. Unchanged cobimetinib and M16 (glycine conjugate of hydrolyzed cobimetinib) were the major circulating species, accounting for 20.5% and 18.3% of the drug-related material in plasma up to 48 hours postdose, respectively. Other circulating metabolites were minor, accounting for less than 10% of drug-related material in plasma. The total recovery of the administered radioactivity was 94.3% (±1.6%, S.D.) with 76.5% (±2.3%) in feces and 17.8% (±2.5%) in urine. Metabolite profiling indicated that cobimetinib had been extensively metabolized with only 1.6% and 6.6% of the dose remaining as unchanged drug in urine and feces, respectively. In vitro phenotyping experiments indicated that CYP3A4 was predominantly responsible for metabolizing cobimetinib. From this study, we concluded that cobimetinib had been well absorbed (fraction absorbed, Fa = 0.88). Given this good absorption and the previously determined low hepatic clearance, the systemic exposures were lower than expected (bioavailability, F = 0.28). We hypothesized that intestinal metabolism had strongly attenuated the oral bioavailability of cobimetinib. Supporting this hypothesis, the fraction escaping gut wall elimination (Fg) was estimated to be 0.37 based on F and Fa from this study and the fraction escaping hepatic elimination (Fh) from the absolute bioavailability study (F = Fa × Fh × Fg). Physiologically based pharmacokinetics modeling also showed that intestinal clearance had to be included to adequately describe the oral profile. These collective data suggested that cobimetinib was well absorbed following oral administration and extensively metabolized with intestinal first-pass metabolism contributing to its disposition. PMID:26451002

  20. Coordinacy of lysosomal enzyme excretion in human urine.

    PubMed Central

    Paigen, K; Peterson, J

    1978-01-01

    Assay conditions have been developed for the determination of urinary beta-glucuronidase, beta-galactosidase, alpha-galactosidase, and beta-hexosaminidase using fluorometric substrates. The assay conditions for beta-glucuronidase overcome interference by both low and high molecular weight inhibitors, a problem that has confused earlier studies of enzyme excretion. The four lysosomal enzymes are excreted corrdinately: although their absolute levels (in units per milligram of creatinine) vary during the day and from one day to the next, the ratio of one enzyme to another remains relatively constant. The lack of correlation betweem plasma and urine enzyme levels, together with the high molecular weights of these enzymes, suggests that the urinary enzymes are not derived by glomerular filtration. The lack of coordinacy with lactate dehydrogenase suggests they are not derived from exfoliated cells. by analogy with experimental animals, they may be derived from lysosomes extruded into the lumen of the proximal tubule by epithelial cells. There is considerable variation among a population of 125 healthy adult subjects for total enzyme excretion. Both total enzyme excretion and coordinacy ratios are log-normally distributed, suggesting that they are the resultants of many factors, each of which has a relative, or proportional, effect on enzyme excretion. About one-half the population variation resides in a process common to the excretion of all four enzymes (possibly the lysosome extrusion pathway), and about one-half resides in factors affecting each enzyme independently. PMID:25285

  1. Empagliflozin (BI 10773), a Potent and Selective SGLT2 Inhibitor, Induces Dose-Dependent Glucosuria in Healthy Subjects.

    PubMed

    Seman, Leo; Macha, Sreeraj; Nehmiz, Gerhard; Simons, Gudrun; Ren, Bailuo; Pinnetti, Sabine; Woerle, Hans J; Dugi, Klaus

    2013-04-01

    Empagliflozin is an orally available, selective inhibitor of sodium glucose cotransporter 2. In this study, single oral doses of empagliflozin from 0.5 to 800 mg were not associated with any clinically significant safety concerns in healthy male volunteers. The incidence of adverse events (AEs) was similar in subjects receiving placebo (22.2%) or empagliflozin (25.0%) in the single rising dose part of the study and after 50 mg empagliflozin under fed (28.6%) or fasted (28.6%) conditions. The most frequent AE was headache. No clinically relevant changes in laboratory or electrocardiogram (ECG) measurements were observed. Single oral doses of empagliflozin were rapidly absorbed, reaching peak levels after 1.0-2.1 hours. Increases in empagliflozin exposure were roughly dose-proportional and a dose-dependent increase in urinary glucose excretion was observed for empagliflozin doses up to 100 mg. After ingestion of 50 mg empagliflozin in conjunction with a high-fat, high-calorie meal, no clinically relevant changes in exposure were found, indicating that empagliflozin can be administered independent of food. Empagliflozin up to 800 mg did not generate clinically significant safety concerns in healthy male subjects. The pharmacokinetic properties of empagliflozin support once daily administration independent of food. PMID:27121669

  2. Multiple-dose acetaminophen pharmacokinetics.

    PubMed

    Sahajwalla, C G; Ayres, J W

    1991-09-01

    Four different treatments of acetaminophen (Tylenol) were administered in multiple doses to eight healthy volunteers. Each treatment (325, 650, 825, and 1000 mg) was administered five times at 6-h intervals. Saliva acetaminophen concentration versus time profiles were determined. Noncompartmental pharmacokinetic parameters were calculated and compared to determine whether acetaminophen exhibited linear or dose-dependent pharmacokinetics. For doses less than or equal to 18 mg/kg, area under the curve (AUC), half-life (t1/2), mean residence time (MRT), and ratio of AUC to dose for the first dose were compared with the last dose. No statistically significant differences were observed in dose-corrected AUC for the first or last dose among subjects or treatments. Half-lives and MRT were not significantly different among treatments for the first or the last dose. Statistically significant differences in t1/2 and MRT were noted (p less than 0.05) among subjects for the last dose. A plot of AUC versus dose for the first and the last doses exhibited a linear relationship. Dose-corrected saliva concentration versus time curves for the treatments were superimposable. Thus, acetaminophen exhibits linear pharmacokinetics for doses of 18 mg/kg or less. Plots of AUC versus dose for one subject who received doses higher than 18 mg/kg were curved, suggesting nonlinear behavior of acetaminophen in this subject. PMID:1800709

  3. Excretion of (3H)prednisolone in clinically normal and experimentally infected bovine udders

    SciTech Connect

    Geleta, J.N.; Shimoda, W.; Mercer, H.D.

    1984-08-01

    The excretion rate of (3H)prednisolone from clinically normal and experimentally infected udders of 10 lactating cows was studied. Each quarter of 6 cows was injected with a single dose of (3H)prednisolone mixed with non-radioactive prednisolone equivalent to 10 mg in 10 ml of peanut oil base. Each of the remaining 4 cows was given 40 mg of nonradioactive prednisolone and (3H)prednisolone in 60% ethanol IV. Control and postadministration samples of blood, milk, and urine were examined for radioactivity. The effects of (3H)prednisolone were evaluated in the same cows, first in clinically normal udders, then 2 weeks later in udders experimentally infected with Streptococcus agalactiae. Absorption and elimination of prednisolone were the same before and after induced infection. Within 3 hours after intramammary injection, 95% of the labeled prednisolone was absorbed systemically, less than 5% of this dose was recovered in milk, and 29% was excreted in urine. After IV injection of (3H)prednisolone, less than 0.2% of the total radioactivity was recovered in milk and less than 46% was excreted in urine. Clinical mastitis induced by S agalactiae was moderate. Circulating blood leukocytes and somatic cells in the milk of normal cows remained essentially unchanged. The leukocyte response to induced infection was rapid in blood and milk. Large numbers of leukocytes were noticed in the milk and a severe leukopenia occurred. Prednisolone treatment did not alter the number of somatic cells in milk or reduce the inflammatory response of experimentally infected cows.

  4. Self-administered treatment for smoking cessation.

    PubMed

    Curry, Susan J; Ludman, Evette J; McClure, Jennifer

    2003-03-01

    Self-administered treatment for smoking cessation has the potential to reach a broad spectrum of the population of smokers. This article focuses on self-administration of behavioral and pharmacological treatments for smoking cessation. Evidence for the effectiveness of written manuals to self-administer behavioral treatment is mixed. There is no evidence that self-help manuals alone are effective. However, they do increase quit rates when combined with personalized adjuncts such as written feedback and outreach telephone counseling. Efficacy trials of first-line pharmacotherapies (nicotine gum, nicotine patch, and bupropion) result in doubling of cessation rates compared to placebo. It is difficult to evaluate the effectiveness of pharmacotherapies when self-administered under real-world conditions. The general consensus is that they improve quit rates, although poor compliance and early discontinuation reduce their effectiveness. Areas for further research include randomized trials of the use of new technologies (e.g., hand-held computers and the Internet) to disseminate self-administered treatments as well as improved surveillance of the use of self-administered treatment in population-based health surveys. PMID:12579547

  5. Urinary calcium excretion in postmenopausal African American women

    PubMed Central

    Aloia, John F.; Shieh, Albert; Mikhail, Mageda; Islam, Shahidul

    2015-01-01

    Aim: The objective of this study was to develop a reference range for urine calcium excretion (both 24-hour and fasting) for African American women compared to White women. In addition, the variables that determine urine calcium excretion were identified. Material: Data were analyzed for baseline studies of healthy postmenopausal volunteers who participated in seven separate studies conducted at one site. Methods: Some studies included fasting urine Ca/Cr and others 24-hour urine calcium excretion. 24-hour urine calcium was considered with and without correction for urinary creatinine excretion. Calcium was measured initially by atomic absorption spectrophotometry and more recently by an automated method (ADVIA 2400 Chemistry System). Results: Participants were considered healthy based on history and physical and routine laboratory studies. Those screened who had a history of nephrolithiasis were excluded. A reference range for 24-hour urine calcium and fasting urine calcium/creatinine was developed. Reference intervals of 11 – 197 mg/24-hour urine calcium excretion and of 0.007 – 0.222 of fasting Ca/Cr were found for African American women compared to 21 – 221 mg/24 hours and 0.019 – 0.264 in White women, respectively. Urine creatinine excretion was higher in African Americans consistent with their higher muscle mass. Conclusion: Urine calcium excretion is lower in postmenopausal African American than White women. The reference range developed should be considered in the diagnosis of hypocalciuric states and may also be useful in the diagnosis of hypercalciuria. PMID:26226948

  6. Contribution of dietary oxalate to urinary oxalate excretion

    NASA Technical Reports Server (NTRS)

    Holmes, R. P.; Goodman, H. O.; Assimos, D. G.

    2001-01-01

    BACKGROUND: The amount of oxalate excreted in urine has a significant impact on calcium oxalate supersaturation and stone formation. Dietary oxalate is believed to make only a minor (10 to 20%) contribution to the amount of oxalate excreted in urine, but the validity of the experimental observations that support this conclusion can be questioned. An understanding of the actual contribution of dietary oxalate to urinary oxalate excretion is important, as it is potentially modifiable. METHODS: We varied the amount of dietary oxalate consumed by a group of adult individuals using formula diets and controlled, solid-food diets with a known oxalate content, determined by a recently developed analytical procedure. Controlled solid-food diets were consumed containing 10, 50, and 250 mg of oxalate/2500 kcal, as well as formula diets containing 0 and 180 mg oxalate/2500 kcal. Changes in the content of oxalate and other ions were assessed in 24-hour urine collections. RESULTS: Urinary oxalate excretion increased as dietary oxalate intake increased. With oxalate-containing diets, the mean contribution of dietary oxalate to urinary oxalate excretion ranged from 24.4 +/- 15.5% on the 10 mg/2500 kcal/day diet to 41.5 +/- 9.1% on the 250 mg/2500 kcal/day diet, much higher than previously estimated. When the calcium content of a diet containing 250 mg of oxalate was reduced from 1002 mg to 391 mg, urinary oxalate excretion increased by a mean of 28.2 +/- 4.8%, and the mean dietary contribution increased to 52.6 +/- 8.6%. CONCLUSIONS: These results suggest that dietary oxalate makes a much greater contribution to urinary oxalate excretion than previously recognized, that dietary calcium influences the bioavailability of ingested oxalate, and that the absorption of dietary oxalate may be an important factor in calcium oxalate stone formation.

  7. Preclinical pharmacokinetics, tissue distribution and excretion studies of a novel anti-candidal agent-thiosemicarbazide derivative of isoniazid (TSC-INH) by validated UPLC-MS/MS assay.

    PubMed

    Iqbal, Muzaffar; Ezzeldin, Essam; Bhat, Mashooq A; Raish, Mohammad; Al-Rashood, Khalid A

    2016-01-01

    A simple and sensitive UPLC-MS/MS assay was developed and validated for rapid determination of thiosemicarbazide derivative of isoniazid (TSC-INH), a potent anti-candidal agent in rat plasma, tissues, urine and feces. All biological samples were prepared by protein precipitation method using celecoxib as an internal standard (IS). Chromatographic separation was achieved on Acquity BEH™ C18 (50×2.1 mm, 1.7 μm) column using gradient mobile phase of acetonitrile and water (containing 0.1% formic acid) at flow rate of 0.3 mL/min. The MRM transitions were monitored at m/z 305.00→135.89 for TSC-INH and m/z 380.08→316.03 for IS in ESI negative mode. All validation parameter results were within the acceptable range described in guideline for bioanalytical method validation. The pharmacokinetic study showed that the compound TSC-INH was orally active with 66% absolute bioavailability in rats. It was rapidly absorbed with peak plasma concentration of 1985.92 ng/mL achieved within 1 h after single oral dose (10 mg/kg) administration. TSC-INH exhibited rapid distribution across the body with highest levels in liver and lungs. Penetration in brain tissues suggests that TSC-INH crossed the blood brain barrier. Only 5.23% of the orally administered drug was excreted as unconverted form in urine and feces implying that TSC-INH was metabolized extensively before excretion. With the preliminary knowledge of in vivo pharmacokinetics and disposition properties, this study will be beneficial for further development of compound TSC-INH in future studies. PMID:26355768

  8. Macroscopic and microscopic biodistribution of intravenously administered iron oxide nanoparticles

    NASA Astrophysics Data System (ADS)

    Misra, Adwiteeya; Petryk, Alicia A.; Strawbridge, Rendall R.; Hoopes, P. Jack

    2015-03-01

    Iron oxide nanoparticles (IONP) are being developed for use as a cancer treatment. They have demonstrated efficacy when used either as a monotherapy or in conjunction with conventional chemotherapy and radiation. The success of IONP as a therapeutic tool depends on the delivery of a safe and controlled cytotoxic thermal dose to tumor tissue following activation with an alternating magnetic field (AMF). Prior to clinical approval, knowledge of IONP toxicity, biodistribution and physiological clearance is essential. This preliminary time-course study determines the acute toxicity and biodistribution of 110 nm dextran-coated IONP (iron) in mice, 7 days post systemic, at doses of 0.4, 0.6, and 1.0 mg Fe/ g mouse bodyweight. Acute toxicity, manifested as changes in the behavior of mice, was only observed temporarily at 1.0 mg Fe/ g mouse bodyweight, the highest dose administered. Regardless of dose, mass spectrometry and histological analysis demonstrated over 3 mg Fe/g tissue in organs within the reticuloendotheilial system (i.e. liver, spleen, and lymph nodes). Other organs (brain, heart, lungs, and kidney) had less than 0.5 mg Fe/g tissue with iron predominantly confined to the organ vasculature.

  9. Enterohepatic circulation, urinary excretion and laxative action of some bisacodyl derivatives after intragastric administration in the rat.

    PubMed

    Sund, R B; Songedal, K; Harestad, T; Salvesen, B; Kristiansen, S

    1981-01-01

    Bisacodyl (BIS), the parent diphenol (DES) and its sulphuric acid di-ester (picosulphate = PICO) were given by stomach tube to fasted rats at a dose of 3.1 mumol/100 g rat. Bile was sampled in the periods 0-6, 6-12 and 12-18 hrs after drug administration, and assayed for total diphenol (= free + conjugated) by HPLC. Mean fractions (% of dose +/- S.E.M.) excreted in 5 rats per compound and period were: BIS 74.0 +/- 4.7, 51.9 +/- 7.9 and 30.8 +/- 2.5; DES 41.2 +/-4.3, 46.8 +/- 4.7 and 25.1 +/- 2.5; PICO 9.0 +/- 0.9, 26.0 +/- 5.4 and 19.6 +/- 3.1. Only minor amounts were excreted as free diphenol. Urine samples taken by bladder puncture and assayed as above furthermore showed that the renal excretion of total diphenol was insignificant compared to the amounts excreted in bile. Practically no diphenol was present in urine 0-6 hrs after the administration of PICO. In experiments with BIS and DES at 0.85 mumol/100 g, total diphenol excreted in bile during 0-6 hrs was: BIS 67.1 +/- 2.6 (n = 5); DES: 55.4 +/- 3.0 (5). - The latency time for laxative effect was studied in groups of 10 unfasted rats per compound. cumulative time response curves showed that PICO caused diarrhoea more promptly at 0.85 mumol/100 g than either BIS or DES. In most rats, this delayed action of BIS and DES persisted also at 1.7 mumol/100 g. At 3.1 mumol/100 g, however, the majority of the rats reacted as promptly to these two compounds as to PICO. These results are discussed in relation to the biliary excretion experiments, and interpreted in terms of the relative importance at the different dose levels of: 1. The enterohepatic recirculated fraction, and 2. The non-absorbed fraction, which passes directly to the large intestine. For PICO, the latter fraction is the single determinant of the effect, which is triggered when the di-ester is being hydrolyzed to active diphenol in this part of the GI-tract. PMID:7223440

  10. Silicon balance in human volunteers; a pilot study to establish the variance in silicon excretion versus intake

    PubMed Central

    2014-01-01

    Background Accumulating evidence suggests a role for silicon in optimal connective tissue health. Further proof of its importance/essentiality may be provided by studies involving imposed depletion followed by 29Si challenge to estimate metabolic balance. Prior to conducting these expensive studies, we first established the variance of estimating normal Si excretion versus intake using a single oral dose of typical dietary Si, orthosilicic acid. Methods Healthy volunteers were recruited from Loei Rajabhat University, separated into two matched groups (three males and three females/group) and maintained on a standardized diet for the three study days. One group ingested 500 ml water containing orthosilicic acid (28.9 mg Si) and the other group received 500 ml water alone, all on a fasted stomach. Blood samples and total urine and faeces were collected over the 48 h post-dose period and 24 h before-hand (baseline) and analysed for silicon by inductively coupled plasma optical emission spectrometry. Results Serum Si analysis confirmed the ready absorption of silicon from the orthosilicic acid solution. Mean total urinary and faecal Si excretions over the 24 h post-dose period accounted for 57 ± 9.5% and 39 ± 9.4% of the ingested dose, respectively. Thus in total 96.3 ± 5.8% of the ingested dose was recovered in faecal plus urinary excretions over the 24 h post-dose period. Conclusions We report that in healthy subjects (presumably in Si balance), the ingestion of a soluble dose of dietary Si results in the same quantity (within analytical error) being excreted within 24 h. It is currently not known if this all originated from the dose solution or if there was some exchange with the body Si pool but, given the low variance in these silicon balance data, isotopic studies are now merited. PMID:24405738

  11. Urinary excretion of chromium following ingestion of chromite-ore processing residues in humans: implications for biomonitoring.

    PubMed

    Gargas, M L; Norton, R L; Harris, M A; Paustenbach, D J; Finley, B L

    1994-12-01

    Biomonitoring programs for urinary chromium (Cr) typically attempt to evaluate occupational exposure via the inhalation route. This study investigated whether Cr can be detected in the urine of people following the ingestion of soils that contain relatively high concentrations of chromium in chromite ore processing residue (COPR). To evaluate the reasonableness of using urinary monitoring to assess environmental exposure, six volunteers ingested 400 mg of soil/day (low-dose group), two others ingested 2.0 g of soil/day (high-dose group) for 3 consecutive days, and one person ingested a placebo on each of 3 days. The soil and COPR mixture contained concentrations of total chromium (Cr) and hexavalent chromium [Cr(VI)] of 103 +/- 20 and 9.3 +/- 3.8 mg/kg, respectively. Therefore, the low-dose group ingested 41 micrograms Cr/day [including 3.7 micrograms Cr(VI)] and the high-dose group ingested 206 micrograms Cr/day [including 18.6 micrograms Cr(VI)] on each of 3 consecutive days. All urine samples were collected and analyzed individually for total Cr on the day prior to dosing, during the 3 days of dosing, and up to the first void 48 h after the last dose. No significant increases in urinary Cr excretion were found when background excretion data were compared with data following each of the 3 days of dosing or in daily mean urine concentrations of the high- vs the low-dose groups. It appears that Cr present in a soil and COPR mixture at Cr doses up to 200 micrograms/day is not sufficiently bioavailable for biomonitoring of urine to be informative.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7846309

  12. Human pharmacology of ayahuasca: subjective and cardiovascular effects, monoamine metabolite excretion, and pharmacokinetics.

    PubMed

    Riba, Jordi; Valle, Marta; Urbano, Gloria; Yritia, Mercedes; Morte, Adelaida; Barbanoj, Manel J

    2003-07-01

    The effects of the South American psychotropic beverage ayahuasca on subjective and cardiovascular variables and urine monoamine metabolite excretion were evaluated, together with the drug's pharmacokinetic profile, in a double-blind placebo-controlled clinical trial. This pharmacologically complex tea, commonly obtained from Banisteriopsis caapi and Psychotria viridis, combines N,N-dimethyltryptamine (DMT), an orally labile psychedelic agent showing 5-hydroxytryptamine2A agonist activity, with monoamine oxidase (MAO)-inhibiting beta-carboline alkaloids (harmine, harmaline, and tetrahydroharmine). Eighteen volunteers with prior experience in the use of psychedelics received single oral doses of encapsulated freeze-dried ayahuasca (0.6 and 0.85 mg of DMT/kg of body weight) and placebo. Ayahuasca produced significant subjective effects, peaking between 1.5 and 2 h, involving perceptual modifications and increases in ratings of positive mood and activation. Diastolic blood pressure showed a significant increase at the high dose (9 mm Hg at 75 min), whereas systolic blood pressure and heart rate were moderately and nonsignificantly increased. Cmax values for DMT after the low and high ayahuasca doses were 12.14 ng/ml and 17.44 ng/ml, respectively. Tmax (median) was observed at 1.5 h after both doses. The Tmax for DMT coincided with the peak of subjective effects. Drug administration increased urinary normetanephrine excretion, but, contrary to the typical MAO-inhibitor effect profile, deaminated monoamine metabolite levels were not decreased. This and the negligible harmine plasma levels found suggest a predominantly peripheral (gastrointestinal and liver) site of action for harmine. MAO inhibition at this level would suffice to prevent first-pass metabolism of DMT and allow its access to systemic circulation and the central nervous system. PMID:12660312

  13. Biotransformation of acrolein in rat: excretion of mercapturic acids after inhalation and intraperitoneal injection.

    PubMed

    Linhart, I; Frantík, E; Vodicková, L; Vosmanská, M; Smejkal, J; Mitera, J

    1996-01-01

    Biotransformation of acrolein (ACR) was studied in vivo in the rat following inhalation and ip administration. The major and minor urinary metabolites were 3-hydroxypropylmercapturic acid (HPMA) and 2-carboxyethylmercapturic acid (CEMA), respectively. Male Wistar rats were exposed to ACR, 23, 42, 77 and 126 mg/m3, for 1 hr. The sum of mercapturic acids HPMA and CEMA excreted within 24 hr after the exposure amounted to 0.87 +/- 0.12, 1.34 +/- 0.5, 2.81 +/- 1.15, and 7.13 +/- 1.56 mumol/kg, i.e., 10.9 +/- 1.5, 13.3 +/- 5.0, 16.7 +/- 6.9, and 21.5 +/- 4.8% of the estimated absorbed dose, respectively. The dose estimate was based on reported values of minute respiratory volume and respiratory tract retention and was corrected for the ACR-induced changes in minute respiratory volume. In the relevant dose range (8.9 to 35.7 mumol/kg) the portion of mercapturic acids excreted was nearly constant for ip exposed rats. The sum of HPMA and CEMA amounted to 29.1 +/- 6.5% of the dose. These results indicate that the deficiency in rat lung metabolism of ACR to acrylic acid previously observed is not compensated by the other detoxication pathway in vivo, mercapturic acid formation. The health hazard arising from inhalation of ACR is likely to be higher than that from other routes of exposure. PMID:8560469

  14. Urine excretion strategy for stem cell-generated embryonic kidneys

    PubMed Central

    Yokote, Shinya; Matsunari, Hitomi; Iwai, Satomi; Yamanaka, Shuichiro; Uchikura, Ayuko; Fujimoto, Eisuke; Matsumoto, Kei; Nagashima, Hiroshi; Kobayashi, Eiji; Yokoo, Takashi

    2015-01-01

    There have been several recent attempts to generate, de novo, a functional whole kidney from stem cells using the organogenic niche or blastocyst complementation methods. However, none of these attempts succeeded in constructing a urinary excretion pathway for the stem cell-generated embryonic kidney. First, we transplanted metanephroi from cloned pig fetuses into gilts; the metanephroi grew to about 3 cm and produced urine, although hydronephrosis eventually was observed because of the lack of an excretion pathway. Second, we demonstrated the construction of urine excretion pathways in rats. Rat metanephroi or metanephroi with bladders (developed from cloacas) were transplanted into host rats. Histopathologic analysis showed that tubular lumina dilation and interstitial fibrosis were reduced in kidneys developed from cloacal transplants compared with metanephroi transplantation. Then we connected the host animal’s ureter to the cloacal-developed bladder, a technique we called the “stepwise peristaltic ureter” (SWPU) system. The application of the SWPU system avoided hydronephrosis and permitted the cloacas to differentiate well, with cloacal urine being excreted persistently through the recipient ureter. Finally, we demonstrated a viable preclinical application of the SWPU system in cloned pigs. The SWPU system also inhibited hydronephrosis in the pig study. To our knowledge, this is the first report showing that the SWPU system may resolve two important problems in the generation of kidneys from stem cells: construction of a urine excretion pathway and continued growth of the newly generated kidney. PMID:26392557

  15. Short communication: Evaluation of nitrogen excretion equations from cattle.

    PubMed

    Johnson, A C B; Reed, K F; Kebreab, E

    2016-09-01

    Nitrogen excretion in dairy manure is a precursor for N2O and NH3 formation in livestock housing, manure storage facilities, and after manure is applied to land. Nitrous oxide is a major contributor to greenhouse gas emissions, and reducing N output from dairy production facilities can reduce the amount of anthropogenic N2O entering the atmosphere. The objective of the study was to conduct a comprehensive evaluation of extant prediction models for N excretion in feces and urine using extensive literature data. A total of 45 N excretion equations were evaluated for lactating cows, heifers, and nonlactating cows and steers. These equations were evaluated with 215 treatment means from 69 published studies collected over 20 yr from 1995 to 2015. Two evaluation methods were used: the root mean square prediction error and the concordance correlation coefficient. Equations constructed using a more rigorous development process fared better than older extant equations. Equations for heifers and nonlactating cows had greater error of prediction compared with equations used for lactating cows. This could be due to limited amount of data available for construction and evaluation of the equations. Urinary N equations had greater prediction errors than other forms of excretion, possibly due to high variability in urinary N excretion and challenges in urine collection. Fecal N equations had low error bias and reached an acceptable level of precision and accuracy. PMID:27320670

  16. Strongyloides stercoralis larvae excretion patterns before and after treatment.

    PubMed

    Schär, F; Hattendorf, J; Khieu, V; Muth, S; Char, M C; Marti, H P; Odermatt, P

    2014-06-01

    The variability of larval excretion impedes the parasitological diagnosis of Strongyloides stercoralis in infected individuals. We assessed the number of larvae excreted per gram (LPG) stool in 219 samples from 38 infected individuals over 7 consecutive days before and in 470 samples from 44 persons for 21 consecutive days after ivermectin treatment (200 μg kg-1 BW). The diagnostic sensitivity of a single stool sample was about 75% for individuals with low-intensity infections (⩽1 LPG) and increased to 95% for those with high-intensity infections (⩾10 LPG). Doubling the number of samples examined per person increased sensitivity to more than 95%, even for low-intensity infections. There was no indication of a cyclic excretion of larvae. After treatment, all individuals stopped excreting larvae within 3 days. Larvae were not detected during any of the following 18 days (total 388 Baermann and 388 Koga Agar tests). Two stool samples, collected on consecutive days, are recommended in settings where low or heterogeneous infection intensities are likely. In this way, taking into account the possible biological variability in excretion, the efficacy of ivermectin treatment can be assessed as soon as 4 days after treatment. PMID:24534076

  17. Urine excretion strategy for stem cell-generated embryonic kidneys.

    PubMed

    Yokote, Shinya; Matsunari, Hitomi; Iwai, Satomi; Yamanaka, Shuichiro; Uchikura, Ayuko; Fujimoto, Eisuke; Matsumoto, Kei; Nagashima, Hiroshi; Kobayashi, Eiji; Yokoo, Takashi

    2015-10-20

    There have been several recent attempts to generate, de novo, a functional whole kidney from stem cells using the organogenic niche or blastocyst complementation methods. However, none of these attempts succeeded in constructing a urinary excretion pathway for the stem cell-generated embryonic kidney. First, we transplanted metanephroi from cloned pig fetuses into gilts; the metanephroi grew to about 3 cm and produced urine, although hydronephrosis eventually was observed because of the lack of an excretion pathway. Second, we demonstrated the construction of urine excretion pathways in rats. Rat metanephroi or metanephroi with bladders (developed from cloacas) were transplanted into host rats. Histopathologic analysis showed that tubular lumina dilation and interstitial fibrosis were reduced in kidneys developed from cloacal transplants compared with metanephroi transplantation. Then we connected the host animal's ureter to the cloacal-developed bladder, a technique we called the "stepwise peristaltic ureter" (SWPU) system. The application of the SWPU system avoided hydronephrosis and permitted the cloacas to differentiate well, with cloacal urine being excreted persistently through the recipient ureter. Finally, we demonstrated a viable preclinical application of the SWPU system in cloned pigs. The SWPU system also inhibited hydronephrosis in the pig study. To our knowledge, this is the first report showing that the SWPU system may resolve two important problems in the generation of kidneys from stem cells: construction of a urine excretion pathway and continued growth of the newly generated kidney. PMID:26392557

  18. Changes in parasite transmission stage excretion after pheasant release.

    PubMed

    Villanúa, D; Acevedo, P; Höfle, U; Rodríguez, O; Gortázar, C

    2006-09-01

    The production of parasite transmission stages was investigated in the faeces of 77 farm-bred ring-necked pheasants (Phasianus colchicus). Coccidian oocysts (Eimeria sp.), and nematode eggs (Heterakis sp., and Capillaria-like eggs) were recovered before and after release but all birds were treated prior to release. Treatment with fenbendazole significantly reduced the abundance of transmission-stage excretion for all parasites, and reduced the prevalence in the case of Eimeria sp. and Heterakis sp. Nonetheless, a significant increase in the excretion abundance for all parasites and in the prevalence of Eimeria sp. and Heterakis sp. was found after release. Eggs of Ascaridia sp. were found only after releasing, suggesting infection ocurred in the wild. A negative relationship was found between the pheasant body condition and Heterakis excretion abundance and a higher abundance of Capillaria sp. eggs in female birds. No significant relationship was found between parasite excretion abundance and pheasant survival. Despite this, results suggest that an increase in the excretion of parasite transmission stages follows the release of captive pheasants into the wild. This can in part explain restocking failures, but also means that autochtonous free-living birds may become exposed to new and potentially harmful pathogens. To avoid these risks it is proposed that improved prophylactic measures should be taken. PMID:16923277

  19. Dogmas and controversies in the handling of nitrogenous wastes: 5-HT2-like receptors are involved in triggering pulsatile urea excretion in the gulf toadfish, Opsanus beta.

    PubMed

    McDonald, M Danielle; Walsh, Patrick J

    2004-05-01

    When injected arterially, serotonin (5-hydroxytryptamine; 5-HT) has been shown to elicit naturally sized urea pulse events in the gulf toadfish, Opsanus beta. The goal of the present study was to determine which 5-HT receptor(s) was involved in mediating this serotonergic stimulation of the pulsatile excretion mechanism. Toadfish were surgically implanted with caudal arterial catheters and intraperitoneal catheters and injected with either 8-OH-DPAT (1 micro mol kg(-1)), a selective 5-HT(1A) receptor agonist, alpha-methyl-5-HT (1 micro mol kg(-1)), a 5-HT(2) receptor agonist, or ketanserin, a 5-HT(2) receptor antagonist (0.01, 0.1, 1 and 10 micro mol kg(-1)) plus alpha-methyl-5-HT. 8-OH-DPAT injection did not mediate an increase in urea excretion, ruling out the involvement of 5-HT(1A) receptors in pulsatile excretion. However, within 5 min, alpha-methyl-5-HT injection caused an increase in the excretion of urea in >95% (N=27) of the fish injected, with an average pulse size of 652+/-102 micro mol N kg(-1) (N=26). With alpha-methyl-5-HT injection there was no corresponding increase in ammonia or [(3)H]PEG 4000 permeability. Urea pulses elicited by alpha-methyl-5-HT were inhibited in a dose-dependent fashion by the 5-HT(2) receptor antagonist ketanserin, which at low doses caused a significant inhibition of pulse size and at higher doses significantly inhibited the occurrence of pulsatile excretion altogether. However, neither 8-OH-DPAT nor alpha-methyl 5-HT injection had an effect on plasma cortisol or plasma urea concentrations. These findings suggest the involvement of a 5-HT(2)-like receptor in the regulation of pulsatile urea excretion. PMID:15143134

  20. Relationship between concentration and exposed area on absorption and excretion of T-2 mycotoxin through rabbit skin

    SciTech Connect

    Wannemacher, R.W. Jr.; Bunner, D.L.; Dinterman, R.E.

    1986-03-01

    T-2 mycotoxin is a severe skin irritant that can be lethal via the dermal route. A non-occlusive barrier model was developed to study the effects of concentration and size of the exposed area on the absorption rate of toxin in rabbit skin. The skin was shaved and, twenty-four hours later, varying concentrations of both (/sup 4/H)-labeled and unlabeled T0 toxin in DMSO were painted on the surface. A barrier, consisting of a mesh-jacketed, half-inch foam pad with a hole in the center, was applied to the skin. In order to assess absorption, lethality and excretion were used as endpoints, and dosage, area, and concentration (..mu.. g/cm/sup 2/) were varied. At doses of 5, 10, and 15 mg/kg of T-2 toxin in DMSO applied to a 200 cm/sup 2/ area, lethality was 0 of 2, 6 of 11, and 6 of 6 rabbits, respectively. This suggests a direct dose-response relationship. However, at a dose of 10 mg/kg applied in a 100 cm/sup 2/ area, there were no deaths in 4 rabbits. This indicates a lower rate of absorption at this higher concentration. The percentage of (/sup 3/H)-toxin excreted was higher at lower doses of T-2 toxin and reduced at higher concentrations. The authors conclude that area, dose, and concentration of applied toxin can influence the amount of T-2 toxin that is absorbed through the skin.

  1. Changes in Medications Administered in Schools

    ERIC Educational Resources Information Center

    McCarthy, Ann Marie; Kelly, Michael W.; Johnson, Shella; Roman, Jaclyn; Zimmerman, M. Bridget

    2006-01-01

    The purpose of this descriptive, cross-sectional study was to determine if there have been changes in the type and number of attention deficit/hyperactivity disorder (AD/HD) medications administered in schools since the introduction of long-acting stimulants. A survey was sent to 1,000 school nurses randomly selected from the National Association…

  2. Teaching Students to Administer the WISC

    ERIC Educational Resources Information Center

    Ritter, Kathleen Yost

    1977-01-01

    A college level psychology course is described in which students were trained by both traditional and experimental methods to administer individual intelligence tests. Comparative analysis of performance by each group indicates that student motivation and performance is not greatly influenced by teaching method and that videotape demonstrations…

  3. Phase I trial of intramuscularly administered tumor necrosis factor in patients with advanced cancer.

    PubMed

    Jakubowski, A A; Casper, E S; Gabrilove, J L; Templeton, M A; Sherwin, S A; Oettgen, H F

    1989-03-01

    A phase I trial of intramuscularly administered recombinant human tumor necrosis factor (rTNF) was conducted in 19 adult patients with advanced solid tumors. The agent was administered daily for up to five consecutive days every other week for two to four courses. Doses of rTNF ranged from 5 to 200 micrograms/m2/d. Dose-limiting toxicities were encountered at doses greater than 100 micrograms/m2/d. Toxicities included tenderness, erythema and induration at the site of injection, fatigue, fever, chills, headache, anorexia, nausea, vomiting, and diarrhea. Moderate to marked reductions in WBC and platelet counts were observed regularly at the highest dose levels, but none were clinically significant. Hepatic enzyme elevation was seen frequently, and two patients developed hyperbilirubinemia. Only one of seven patients treated with doses greater than 100 micrograms/m2/d completed the planned course of therapy. Even at the highest dose levels, serum concentrations of rTNF could only rarely be detected in the serum. No therapeutic responses were observed. The maximal tolerated dose (MTD) of rTNF in this trial was 150 micrograms/m2/d, administered for two courses. PMID:2918329

  4. [Predictors of bacterial excretion in patients with infiltrative pulmonary tuberculosis].

    PubMed

    Volchegorskiĭ, I A; Novoselov, P N; Bolotov, A A

    2009-01-01

    An association of bacterial excretion with the magnitude of the X-ray and clinical symptoms of infiltrative pulmonary tuberculosis, with the intensity of concomitant anxiety-depression disorders and the results of complex laboratory peripheral blood tests was studied in 100 patients with this condition. The fact that M. tuberculosis was present in the sputum was shown to be linked to the significant increase in the size of tuberculous infiltrates, the extent of decay in the latter, their connection with the root of the lung, the spread of excretion foci, and the intensity of cough and bloody expectoration. The similar trend was demonstrated in the degree of situational anxiety, depressive indecision, and pessimism, as well as in the values of leukocytosis and erythrocyte sedimentation rate. The predictive informative value of a set of findings is illustrated by the discriminant function equation that allows the correct prediction of bacterial excretion in 76.8% of cases. PMID:20095373

  5. Quantitation of phosphorus excretion in sheep by compartmental analysis

    SciTech Connect

    Schneider, K.M.; Boston, R.C.; Leaver, D.D.

    1987-04-01

    The control of phosphorus excretion in sheep has been examined by constructing a kinetic model that contains a mechanistic set of connections between blood and gastrointestinal tract. The model was developed using experimental data from chaff-fed sheep and gives an accurate description of the absorption and excretion of /sup 32/P phosphorus in feces and urine of the ruminating sheep. These results indicated the main control site for phosphorus excretion in the ruminating sheep was the gastrointestinal tract, whereas for the non-ruminating sheep fed the liquid diet, control was exerted by the kidney. A critical factor in the induction of adaptation of phosphorus reabsorption by the kidney was the reduction in salivation, and since this response occurred independently of marked changes in the delivery of phosphorus to the kidney, a humoral factor may be involved in this communication between salivary gland and kidney.

  6. Pharmacokinetics, metabolism, and excretion of (14)C-labeled belinostat in patients with recurrent or progressive malignancies.

    PubMed

    Calvo, Emiliano; Reddy, Guru; Boni, Valentina; García-Cañamaque, Lina; Song, Tao; Tjornelund, Jette; Choi, Mi Rim; Allen, Lee F

    2016-04-01

    Background Belinostat, a potent pan-inhibitor of histone deacetylase (HDAC) enzymes, is approved in the United States (US) for relapsed/refractory peripheral T-cell lymphoma. In nonclinical studies, bile and feces were identified as the predominant elimination routes (50-70 %), with renal excretion accounting for ~30-50 %. A Phase 1 human mass balance study was conducted to identify species-dependent variations in belinostat metabolism and elimination. Methods Patients received a single 30-min intravenous (IV) infusion of (14)C-labeled belinostat (1500 mg). Venous blood samples and pooled urine and fecal samples were evaluated using liquid chromatography - tandem mass spectroscopy for belinostat and metabolite concentrations pre-infusion through 7 days post-infusion. Total radioactivity was determined using liquid scintillation counting. Continued treatment with nonradiolabled belinostat (1000 mg/m(2) on Days 1-5 every 21 days) was permitted. Results Belinostat was extensively metabolized and mostly cleared from plasma within 8 h (N = 6), indicating that metabolism is the primary route of elimination. Systemic exposure for the 5 major metabolites was >20 % of parent, with belinostat glucuronide the predominant metabolite. Mean recovery of radioactive belinostat was 94.5 % ± 4.0 %, with the majority excreted within 48 and 96 h in urine and feces, respectively. Renal elimination was the principal excretion route (mean 84.8 % ± 9.8 % of total dose); fecal excretion accounted for 9.7 % ± 6.5 %. Belinostat was well tolerated, with mostly mild to moderate adverse events and no treatment-related severe/serious events. Conclusion Mass balance was achieved (~95 % mean recovery), with metabolism identified as the primary route of elimination. Radioactivity was predominantly excreted renally as belinostat metabolites. PMID:26769244

  7. Recommendation to Exclude Bile-Duct-Cannulated Rats with Hyperbilirubinemia for Proper Conduct of Biliary Drug Excretion Studies.

    PubMed

    Kato, Koji; Hasegawa, Yoshitaka; Iwata, Katsuya; Ichikawa, Takuya; Yahara, Tohru; Tsuji, Satoshi; Sugiura, Masayuki; Yamaguchi, Jun-Ichi

    2016-08-01

    Hyperbilirubinemia (HB) is sometimes encountered following bile-duct cannulation in rats. It possibly originates from the reduced functioning of multidrug resistance-associated protein 2 (Mrp2) and subsequent adaptive alterations in the expression of Mrp3 and the organic anion transporting polypeptides (Oatps). Our aim was to clarify the importance of excluding bile-duct-cannulated (BDC) rats with HB for proper conduct of drug excretion studies. We detected HB [serum total bilirubin concentration (TBIL) ≥0.20 mg/dl] in 16% of all BDC rats prepared. The serum activities of aspartate aminotransferase, alanine aminotransferase, leucine aminopeptidase, and alkaline phosphatase were within the respective normal ranges in the BDC rats with mild HB (TBIL, 0.20-0.79 mg/dl), indicating the absence of hepatic failure. In the pharmacokinetics of pravastatin, an Oatps/Mrp2 probe drug in the BDC rats, the apparent volume of distribution and the clearance were smaller in the mild HB group as compared with the normal group, suggesting the reduction of apparent hepatic uptake and hepatobiliary elimination. The biliary excretion (percentage of dose) was significantly reduced by 54%, suggesting that the biliary efflux activity via Mrp2 was reduced to a greater extent relative to metabolic activity in hepatocytes. The serum γ-glutamyltransferase (GGT) activity correlated with TBIL and inversely correlated with biliary excretion of pravastatin, a finding which could serve as a clue to uncover the regulatory system involving cooperation between GGT and Mrp2. In conclusion, BDC rats with HB, however mild, should be excluded from drug excretion studies to avoid the risk of underestimation of the biliary excretion of drugs. PMID:27208382

  8. Distribution and metabolism of intravenously administered choline[methyl- 3-H] and synthesis in vivo of acetylcholine in various tissues of guinea pigs.

    PubMed

    Haubrich, D R; Wang, P F; Wedeking, P W

    1975-04-01

    The biosynthesis of acetylcholine and the fate of intravenously administered choline [methyl- 3-H] were studied in guinea pigs anesthetized with pentobarbital. Choline and acetylcholine were isolated by paper electrophoresis and estimated by use of a specific enzymatic (choline kinase) - radioisotopic assay. The concentration of acetylcholine ranged from 25.5 to 1.1 nmol/g in the following tissues (in order of decreasing concentration): duodenum, corpus striatum, stomach, cerebral cortex, spinal cord, abdominal fat, submaxillary gland, kidney, adrenal gland, spleen, liver, lung, heart and diaphragm. Choline [methyl- 3-H] was converted in the tissues to acetylcholine within 3 minutes after intravenous administration of the precursor. Virtually all the radioactivity in plasma at that time was present as free choline, suggesting that free choline from plasma is the immediate precursor for acetylcholine synthesized in the tissues cited. The concentration of free choline in tissues ranged from 344 nmol/g in adrenals to 40 nmol/g in heart, while that in plasma was 15 nmol/g. The initial half-life of choline in plasma, estimated from the rate of disappearance of choline after intravenous administration of either a tracer dose of choline [methyl- 3-H] (0.031 mumol/kg) or a high dose of choline chloride (200 mumol/kg), was less than 1 minute. This rapid removal of choline from plasma resulted from uptake (or binding) by tissues, with kidney and liver removing about 50% of the administered dose of choline [methyl- 3-H] within 3 minutes after its administration. Uptake of choline occurred in all tissues cited above, but there was a 20-fold difference in the uptake by the most active tissues (kidney and adrenals), as compared to that of the least active (central nervous system). Within 60 minutes after administration of choline [methyl- 3-H], most of the radioactive choline taken up by tissues had been converted to organic-soluble metabolites and to water-soluble metabolites

  9. Nocturnal 6-hydroxymelatonin sulfate excretion in female workers exposed to magnetic fields

    SciTech Connect

    Juutilainen, J; Stevens, Richard G. ); Anderson, Larry E. ); Hansen, Norman H.; Kilpelainen, M; Kumlin, T; Laitinen, J T.; Sobell, Eugene; Wilson, Bary W. )

    2000-03-15

    The objective of this study was to determine whether daytime occupational exposure to extremely low frequency magnetic fields (MFs) suppresses nocturnal melatonin production. Sixty female volunteers were recruited. Thirty-nine worked in a garment factory, and 21 office workers served as a reference group. Exposure assessment was based on the type of sewing machine used and MF measurements around each type of machine. Eye-level MF flux density was used to classify the operators to higher (> 1 microT) and lower (0.3-1 microT) exposure categories. A third group of factory workers had diverse MF exposures from other sources. The reference group had average exposure of about 0.15 microT. Urine samples were collected on Friday and Monday for three consecutive weeks. Melatonin production was assessed as urinary 6-hydroxymelatonin sulfate (6-OHMS) excretion. The ratio of Friday morning/Monday morning 6-OHMS was used to test the hypothesis that melatonin production is suppressed after 4 days of occupational MF exposure with significant recovery during the weekend. Possible chronic suppression of melatonin production was evaluated by studying exposure-related differences in the Friday values by multivariate regression analysis. The Monday/Friday ratios were close to 1.0, suggesting that there is no increase in melatonin production over the weekend. The average 6-OHMS excretion on Friday was lower among the factory workers than in the reference group, but no monotonous dose-response was observed. Multivariate regression analysis identified MF exposure, smoking, and age as significant explanatory variables associated with decreased 6-OHMS excretion.

  10. Hepatically-metabolized and -excreted artificial oxygen carrier, hemoglobin vesicles, can be safely used under conditions of hepatic impairment

    SciTech Connect

    Taguchi, Kazuaki; Miyasato, Mayumi; Ujihira, Hayato; Watanabe, Hiroshi; Kadowaki, Daisuke; Sakai, Hiromi; Tsuchida, Eishun; Horinouchi, Hirohisa; Kobayashi, Koichi; Maruyama, Toru; Otagiri, Masaki

    2010-11-01

    The hemoglobin vesicle (HbV) is an artificial oxygen carrier in which a concentrated Hb solution is encapsulated in lipid vesicles. Our previous studies demonstrated that HbV is metabolized by the mononuclear phagocyte system, and the lipid components are excreted from the liver. It is well-known that many hepatically-metabolized and -excreted drugs show altered pharmaceutics under conditions of liver impairment, which results in adverse effects. The aim of this study was to determine whether the administration of HbV causes toxicity in rats with carbon tetrachloride induced liver cirrhosis. Changes in plasma biochemical parameters, histological staining and the pharmacokinetic distribution of HbV were evaluated after an HbV injection of the above model rats at a putative clinical dose (1400 mgHb/kg). Plasma biochemical parameters were not significantly affected, except for a transient elevation of lipase, lipid components and bilirubin, which recovered within 14 days after an HbV infusion. Negligible morphological changes were observed in the kidney, liver, spleen, lung and heart. Hemosiderin, a marker of iron accumulation in organs, was observed in the liver and spleen up to 14 days after HbV treatment, but no evidence of oxidative stress in the plasma and liver were observed. HbV is mainly distributed in the liver and spleen, and the lipid components are excreted into feces within 7 days. In conclusion, even under conditions of hepatic cirrhosis, HbV and its components exhibit the favorable metabolic and excretion profile at the putative clinical dose. These findings provide further support for the safety and effectiveness of HbV in clinical settings.

  11. Administering social security: challenges yesterday and today.

    PubMed

    Puckett, Carolyn

    2010-01-01

    In 2010, the Social Security Administration (SSA) celebrates the 75th anniversary of the passage of the Social Security Act. In those 75 years, SSA has been responsible for programs providing unemployment insurance, child welfare, and supervision of credit unions, among other duties. This article focuses on the administration of the Old-Age, Survivors, and Disability Insurance program, although it also covers some of the other major programs SSA has been tasked with administering over the years-in particular, Medicare, Black Lung benefits, and Supplemental Security Income. The article depicts some of the challenges that have accompanied administering these programs and the steps that SSA has taken to meet those challenges. Whether implementing complex legislation in short timeframes or coping with natural disasters, SSA has found innovative ways to overcome problems and has evolved to meet society's changing needs. PMID:20737858

  12. Excretion of radioactivity following the intraperitoneal administration of /sup 14/C-DDT, /sup 14/C-DDD, /sup 14/C-DDE and /sup 14/C-DDMU to the rat and Japanese Quail

    SciTech Connect

    Fawcett, S.C.; Bunyan, P.J.; Huson, L.W.; King, L.J.; Stanley, P.I.

    1981-09-01

    A study in progress to examine the metabolic fate of DDT in birds and mammals is discussed. The first phase of the study, which is reported in this article, has been to establish the rate of excretion of ratioactivity following the intraperitoneal administrations of /sup 14/C-DDT, /sup 14/C-DDE, /sup 14/C-DDD, and /sup 14/C-DDMU to male rats and male Japanese quail. The mean values from the three animals in each experimental group for the amount of radioactivity excreted daily are given, and it was found that the rats excreted the radioactivity administered as DDT, DDD, and DDE substantially faster than did the quail. DDMU was excreted relatively rapidly and at similar rates. This finding suggests that apparent differences in the rates of excretion of DDT by birds and mammals probably arise from differences in the conversion of DDT to DDD or DDE or in the degradation of these metabolites to DDMU. The Japanese quail differ from the rats in excreting substantial amounts of unchanged DDT, DDE, and DDD, which probably reflects the inability of the Japanese quail to readily metabolise these compounds.

  13. Studies on the excretion of diazepam and nordazepam into milk for the prediction of milk-to-plasma drug concentration ratios.

    PubMed

    Stebler, T; Guentert, T W

    1992-10-01

    The influence of varying protein and fat content in milk of New Zealand White rabbits on the milk-to-plasma drug concentration (M/P) ratio of diazepam was studied. At various time points after littering, a bolus dose (1.5 mg/kg) followed by a 26-hr infusion (1.8 mg/h) of diazepam was administered to freely moving rabbits via a jugular vein catheter. Milk and blood samples were collected to allow characterization of milk composition and quantitative determination of diazepam and nordazepam in milk and plasma. At steady state diazepam showed M/P ratios between 3.7 and 9.5, whereas nordazepam showed ratios between 2.1 and 4.3, respectively. The relative importance of milk protein binding and milk-fat partitioning for the excretion of a drug into milk depended on the drug's affinity to milk fat. A stepwise multiple regression analysis suggested that observed M/P ratios of diazepam could be explained by considering the fat content of milk alone. Nordazepam with a lower solubility in milk fat showed M/P ratios which could be best explained by considering protein and fat concentrations together. Using the data from the infusion studies, two recently published diffusional models to predict M/P ratios were evaluated. Neither model could accurately predict the M/P ratios of diazepam and nordazepam observed in rabbits. However, after extending the model described by Atkinson and Begg to take the actually measured partitioning between skim milk and milk fat into account, a great improvement in the predictive power for observed M/P ratios occurred.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1448430

  14. Manure Nutrient Excretion by Jersey and Holstein Cows

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective was to evaluate feces, urine, and nitrogen (N) excretion by Jersey and Holstein cows. Sixteen multiparous cows (n=8 per breed) were fed two experimental rations at calving in a switchback experimental design. Diets were 50% forage and based on corn meal (control) or whole cottonseed. H...

  15. The absorption and excretion of fluoride and arsenic in humans.

    PubMed

    Zheng, Yujian; Wu, Jiyao; Ng, Jack C; Wang, Guoquan; Lian, Wu

    2002-07-01

    The absorption and excretion of fluoride and arsenic were measured in a group of healthy volunteers given drinking water with naturally high concentration of fluoride (F 2.3 mg/l)(,) or high concentration of arsenic (As 0.15 mg/l), or high concentrations of both fluoride and arsenic (F 2.25 mg/l, As 0.23 mg/l and F 4.05 mg/l, As 0.58 mg/l), respectively. The results indicated that, for arsenic, the absorption rate, the proportion of urinary excretion and the biological-half-life did not show statistically significant differences between drinking water containing high arsenic alone and drinking water containing different levels of high arsenic and fluoride. Excretion and retention of arsenic were positively correlated to the total arsenic intake. Similar results were observed for fluoride. This suggests that there are different metabolic processes for arsenic and fluoride in respect to absorption and excretion; and no joint action can be attributed by these two elements. PMID:12076512

  16. Excretion of depleted uranium by Gulf War veterans.

    PubMed

    Toohey, R E

    2003-01-01

    During the Persian Gulf War, in 1991, approximately 100 US military personnel had potential intakes of depleted uranium (DU), including shrapnel wounds. In 1993, the US government initiated a follow-up study of 33 Gulf War veterans who had been exposed to DU, many of whom contained embedded fragments of DU shrapnel in their bodies. The veterans underwent medical evaluation, whole-body counting, and urinalysis for uranium by kinetic phosphorescence analysis (KPA). Data are available from seven individuals who exceeded the detection limit for whole-body counting and also had elevated urinary uranium. Urinary excretion rates, in microg U g(-1) creatinine, were determined in 1997 and 1999. The body contents, in mg DU, were determined in 1997; it is assumed there were no significant decreases in total body content in the interim. For the 1997 data, the mean fractional excretion was (2.4 +/- 2.8) x 10(-5) g(-1) creatinine, and for the 1999 data, the mean was (1.1 +/- 0.6) x 10(-5) g(-1) creatinine. However, these means are not significantly different, nor is there any correlation of excretion rate with body content. Thus, human data available to date do not provide any basis for determining the effects of particle surface area, composition and solubility, and biological processes such as encapsulation, on the excretion rate. PMID:14526951

  17. INFLUENCE OF DIETARY ARSENIC ON URINARY ARSENIC METABOLITE EXCRETION

    EPA Science Inventory

    Influence of Dietary Arsenic on Urinary Arsenic Metabolite Excretion

    Cara L. Carty, M.S., Edward E. Hudgens, B.Sc., Rebecca L. Calderon, Ph.D., M.S.P.H., Richard Kwok, M.S.P.H., Epidemiology and Biomarkers Branch/HSD, NHEERL/US EPA; David J. Thomas, Ph.D., Pharmacokinetics...

  18. Renal Regulation of Acid-Base Balance: Ammonia Excretion.

    ERIC Educational Resources Information Center

    Tanner, George A.

    1984-01-01

    Describes an experiment which demonstrates changes in ammonia excretion and urine pH that occur in response to metabolic acidosis (induced by ammonium chloride ingestion) or metabolic alkalosis (produced by sodium bicarbonate ingestion). List of materials needed and background information are included. Typical results are provided and discussed.…

  19. Association between consumption of cruciferous vegetables and condiments and excretion in urine of isothiocyanate mercapturic acids.

    PubMed

    Vermeulen, Martijn; van den Berg, Robin; Freidig, Andreas P; van Bladeren, Peter J; Vaes, Wouter H J

    2006-07-26

    A high intake of cruciferous vegetables is associated with a reduced risk of cancer and cardiovascular diseases. This protective effect has been linked to isothiocyanates, enzymatic hydrolysis products of glucosinolates. In this study, the metabolic fate of glucosinolates and isothiocyanates after ingestion of 19 different cruciferous vegetables was studied in three male subjects. After the consumption of 13 cruciferous vegetables (glucosinolate content, 0.01-0.94 mmol/kg) and six condiments (isothiocyanate content, 0.06-49.3 mmol/kg), eight different isothiocyanate mercapturic acids were determined in urine samples. Excretion levels after the consumption of raw vegetables and condiments were higher (bioavailability, 8.2-113%) as compared to cooked vegetables (bioavailability, 1.8-43%), but the excretion rate was similar (t1/2=2.1-3.9 h). Isothiocyanates in urine remain longer at a nonzero level after the consumption of glucosinolates from cooked vegetables, as compared to raw vegetables and condiments, and maximal levels in urine were reached about 4 h later. Isothiocyanate mercapturic acids can be used as a biomarker to reflect the active dose of isothiocyanates absorbed. PMID:16848516

  20. Urinary guanidinoacetic acid excretion as an indicator of gentamicin nephrotoxicity in rats.

    PubMed

    Kiyatake, Ikuo; Nakamura, Tsukasa; Koide, Hikaru

    2004-07-01

    The kidney is the main site of guanidinoacetic acid synthesis and excretion. The aim of this study was to examine whether urinary guanidinoacetic acid is a sensitive indicator for diagnosis of early-stage gentamicin nephrotoxicity. Early-stage renal injury was induced in rats by a single intravenous injection of 5, 10, or 30 mg/kg body weight gentamicin. Twenty-four hours after injection all rats were killed. Blood, urine and tissue guanidino compound concentrations were determined by high performance liquid chromatography. Glycine amidinotransferase activity in tissues was assayed according to the method of Pilsum. Urinary guanidinoacetic acid excretion was decreased in 5 mg/kg gentamicin-treated rats in comparison to that in control rats, whereas urine N-acetyl-beta-D-glucosaminidase activity and beta2-microglobulin were unchanged. Guanidinoacetic acid concentration and glycine amidinotransferase activity in the kidney were significantly decreased in 5, 10, and 30 mg/kg gentamicin-treated rats; the decreases were dose-dependent. These results suggest that the urine guanidinoacetic acid concentration is a more sensitive indicator of renal injury than conventional indicators such as urine N-acetyl-beta-D-glucosaminidase and beta2-microglobulin. PMID:15462098

  1. Plutonium excretion in urine of residents living near the Rocky Flats Environmental Technology Site.

    PubMed

    Ibrahim, S A; Whicker, F W; Reuss, S K; Whicker, R D; Chapman, P L; Krahenbuhl, M P

    1999-04-01

    An assessment of current levels of 239Pu in individuals living near the Rocky Flats Environmental Technology Site was conducted. Long-term residents of areas adjacent to the Site, as well as people living well beyond any expected influence of the site, provided urine samples, which were analyzed by fission track analysis for the levels of 239Pu. The Rocky Flats Environmental Technology Site vicinity participants were selected for maximum possible exposure to environmental plutonium by virtue of residence location, length of residence, age, and outdoor lifestyle. The mean 239Pu excretion rate in urine estimated for the entire Rocky Flats group was 1.1 microBq d(-1), in contrast to that estimated for the background group (0.85 microBq d(-1)). The estimated median 239Pu excretion rate for the Rocky Flats group was 1.1 microBq d(-1), compared to 0.54 microBq d(-1) for the background group. Both parametric and non-parametric tests indicated that these differences were not statistically significant (alpha = 0.05). Measured levels of 239Pu in urine from the Rocky Flats group were low and well within the range of reported "background" values, indicating small doses and low health risks. The fission track analysis technique may not be sufficiently accurate or precise to allow definitive comparisons between two groups of subjects with near-background levels of 239Pu in urine. PMID:10086597

  2. Role of liver lysosomes in uptake and biliary excretion of manganese in mice

    SciTech Connect

    Suzuki, H.; Wada, O.

    1981-12-01

    To determine the mechanism of manganese excretion from the liver into bile, manganese content in blood, bile, whole liver, and subcellular fractions of liver was measured following intraperitoneal injection of a single dose of manganese (49 mg Mn(OAc)/sub 2/. 4H/sub 2/O/kg body wt) in mice. Manganese in blood was rapidly incorporated into liver and appeared in bile within hours. Most of the absorbed manganese in liver was recovered in the mitochondrial-lysosomal fraction. Purified nuclei contained only one-tenth of the manganese found in the crude nuclear fraction. Sucrose density gradient centrifugation revealed that lysosomes took up and released manganese more rapidly than mitochondria. Also, manganese content in the liver and bile decreased following pretreatment with trypan blue. These values returned to normal with simultaneous administration of cortisone. Manganese released in vitro from the mitochondrial-lysosomal fraction and manganese in bile were measured as manganese acetate by gel filtration. The results suggest that liver lysosomes play an important role in intrahepatic movement and affect biliary excretion of absorbed manganese.

  3. Chronic effects of lead on renin and renal sodium excretion. [Rats

    SciTech Connect

    Fleischer, N.; Mouw, D.R.; Vander, A.J.

    1980-05-01

    Rats were chronically give 0.5 mg/ml Pb in drinking water. This produced blood and renal lead concentratoins of approximately 30 )g/dl and 20)g/gm, respectively, significant kidney swelling, but no change in body weight or hematocrit. After 6 weeks of Pb treatment and during ingestion of a sodium-free diet, plasma, renin activity (PRA) was elevated (controls: same diet, no lead), but there was no change in plasma resin substrate (PRS). After 5 months the PRA was significantly higher in the lead-treated group even on a 1% NaCl diet, but the difference between groups disappeared on an Na-free diet; that is, the renin response to sodium deprivation was blunted. As early as 6 weeks after beginning lead treatment, the treated group manifested reduced ability to decrease Na excretion following removal of NaCl from the diet; steady-state sodium excretion was normal on either the 1% NaCl or Na-free diet. We conclude that changes in the renin angiotensin system and renal sodium handling may be important toxic effects of low doses of lead on the kidneys of rats.

  4. Absorption, distribution, and excretion of 8-methoxypsoralen in HRA/Skh mice

    SciTech Connect

    Muni, I.A.; Schneider, F.H.; Olsson, T.A. III; King, M.

    1984-12-01

    The tissue distribution and excretion of (/sup 3/H)8-methoxypsoralen (8-MOP), a well-accepted therapeutic agent for the treatment of psoriasis, was studied in hairless HRA/Skh female mice. Mice were given single oral doses of 6 mg of (/sup 3/H)8-MOP or 5-(/sup 14/C)8-MOP/kg in corn oil. Radiochemical analyses of tissues and excreta were accomplished by liquid scintillation counting. The 8-MOP appeared to be rapidly absorbed through the gastrointestinal tract, where the tritium levels were highest, followed by skin, blood, and liver; levels were lowest in fat (adipose tissue). In female HRA/Skh mice which had not been irradiated with UVA (320-400 nm), 84% of the carbon-14 and 58% of the tritium were recovered in the urine and feces within 24 hours of oral administration of 5-(/sup 14/C)8-MOP or (/sup 3/H)8-MOP, respectively. Animals that were exposed to UVA and received (3H)8-MOP excreted approximately 12% less tritium in the urine and feces compared with the animals which received no UVA.

  5. Hair analysis for drugs of abuse. VI. The excretion of methoxyphenamine and methamphetamine into beards of human subjects.

    PubMed

    Nakahara, Y; Takahashi, K; Konuma, K

    1993-12-01

    The excretion of methoxyphenamine (MOP) and methamphetamine (MA) into beards has been studied. Six healthy male subjects orally took 50 mg of MOP at a single dose and 7 doses for a successive 7 days. Their beard hairs were collected by an electric shaver every morning until MOP disappeared from the beard. After washing with 0.1% SDS, the beard samples were extracted with methanol-5 N HCl (20:1) under ultra-sonication for 1 h and the solution was kept overnight. MOP in the extract was determined by GC/MS using deuterium labelled MOP as an internal standard after trifluoroacetyl-derivatization. The drug concentrations in beard and the reproducibility of analysis were compared with the three procedures, unwashed, 0.1% SDS (wash I) and the additional ethanol (wash II) wash. The drug concentration in beard after SDS wash was 0.5-2.5 ng/mg lower than that in unwashed beard during the first 5-6 days. The drug concentration in beard after ethanol wash was much lower than that in the unwashed beard. The drug excreted into beard was detected 10 approximately 12 days for a single dose and 12-14 days for 7 doses after the last dosage at the cut off level of 1 ng/mg. On the contrary, the drug excreted in urine was not detected after more than 3 days after use. O-Desmethyl MOP, a major metabolite of MOP, was also detected in beard. The procedures were applied to the detection of MA in beard of MA abusers. It was realized that a beard sample was more useful than a urine sample assuming a longer detection. PMID:7908007

  6. Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers.

    PubMed

    Hirawat, Samit; Welch, Ellen M; Elfring, Gary L; Northcutt, Valerie J; Paushkin, Sergey; Hwang, Seongwoo; Leonard, Eileen M; Almstead, Neil G; Ju, William; Peltz, Stuart W; Miller, Langdon L

    2007-04-01

    Nonsense (premature stop codon) mutations are causative in 5% to 15% of patients with monogenetic inherited disorders. PTC124, a 284-Dalton 1,2,4-oxadiazole, promotes ribosomal readthrough of premature stop codons in mRNA and offers therapeutic potential for multiple genetic diseases. The authors conducted 2 phase I studies of PTC124 in 62 healthy adult volunteers. The initial, single-dose study evaluated doses of 3 to 200 mg/kg and assessed fed-fasting status on pharmacokinetics following a dose of 50 mg/kg. The subsequent multiple-dose study evaluated doses from 10 to 50 mg/kg/dose twice per day (bid) for up to 14 days. PTC124 administered orally as a liquid suspension was palatable and well tolerated through single doses of 100 mg/kg. At 150 and 200 mg/kg, PTC124 induced mild headache, dizziness, and gastrointestinal events. With repeated doses through 50 mg/kg/dose bid, reversible transaminase elevations <2 times the upper limit of normal were sometimes observed. Immunoblot analyses of peripheral blood mononuclear cell extracts revealed no protein elongation due to nonspecific ribosomal readthrough of normal stop codons. PTC124 plasma concentrations exceeding the 2- to 10-microg/mL values associated with activity in preclinical genetic disease models were safely achieved. No sex-related differences in pharmacokinetics were seen. No drug accumulation with repeated dosing was apparent. Diurnal variation was observed, with greater PTC124 exposures after evening doses. PTC124 excretion in the urine was <2%. PTC124 pharmacokinetics were described by a 1-compartment model. Collectively, the data support initiation of phase II studies of PTC124 in patients with nonsense mutation-mediated cystic fibrosis and Duchenne muscular dystrophy. PMID:17389552

  7. An open-label, randomized positron emission tomography (PET) study in healthy male volunteers consisiting of Part A and Part B. Part A: Clinical validation of norepinephrine transporter (NET) PET ligand, (S,S)-[11C]O-methylreboxetine ([11C]MRB) using different doses of oral atomoxetine as NET reuptake inhibitor. Part B: Evaluation of NET occupancy, as measured by [11C]MRB, with multiple dosing regimens of orally administered GSK372475.

    SciTech Connect

    Fowler, Joanna

    2007-08-31

    Results from human studies with the PET radiotracer (S,S)-[(11)C]O-methyl reboxetine ([(11)C](S,S)-MRB), a ligand targeting the norepinephrine transporter (NET), are reported. Quantification methods were determined from test/retest studies, and sensitivity to pharmacological blockade was tested with different doses of atomoxetine (ATX), a drug that binds to the NET with high affinity (K(i)=2-5 nM). METHODS: Twenty-four male subjects were divided into different groups for serial 90-min PET studies with [(11)C](S,S)-MRB to assess reproducibility and the effect of blocking with different doses of ATX (25, 50 and 100 mg, po). Region-of-interest uptake data and arterial plasma input were analyzed for the distribution volume (DV). Images were normalized to a template, and average parametric images for each group were formed. RESULTS: [(11)C](S,S)-MRB uptake was highest in the thalamus (THL) and the midbrain (MBR) [containing the locus coeruleus (LC)] and lowest for the caudate nucleus (CDT). The CDT, a region with low NET, showed the smallest change on ATX treatment and was used as a reference region for the DV ratio (DVR). The baseline average DVR was 1.48 for both the THL and MBR with lower values for other regions [cerebellum (CB), 1.09; cingulate gyrus (CNG) 1.07]. However, more accurate information about relative densities came from the blocking studies. MBR exhibited greater blocking than THL, indicating a transporter density approximately 40% greater than THL. No relationship was found between DVR change and plasma ATX level. Although the higher dose tended to induce a greater decrease than the lower dose for MBR (average decrease for 25 mg=24+/-7%; 100 mg=31+/-11%), these differences were not significant. The different blocking between MBR (average decrease=28+/- 10%) and THL (average decrease=17+/-10%) given the same baseline DVR indicates that the CDT is not a good measure for non-NET binding in both regions. Threshold analysis of the difference between the

  8. A 4-week Repeated Dose Toxicity Study of Glycine in Rats by Gavage Administration

    PubMed Central

    Shibui, Yusuke; Miwa, Tadashi; Yamashita, Mayumi; Chin, Keigi; Kodama, Terutaka

    2013-01-01

    In order to examine the toxicity profile of glycine, an authorized food additive, a solution of glycine in water for injection was administered orally (via gavage) to male SD rats (Crl:CD(SD)) once daily for 4 weeks at doses of 500, 1000 and 2000 mg/kg/day in a volume of 10 mL/kg. Control animals received vehicle only. No animals died, and no glycine-related changes were observed in body weight, food consumption, water consumption, hematology, organ weight, gross pathological examination or histopathological examination. In urinalysis, daily urinary volume and urinary Cl excretion were significantly higher in the 2000 mg/kg/day dose group, and urine pH and urinary protein showed lower trends in the glycine-treated groups. However, these changes were considered to be of little toxicological significance, because there were no histopathological changes in the kidneys or urinary bladder and no changes in other urinary parameters. As regards blood chemistry, phospholipids were significantly higher in the 2000 mg/kg/day dose group. However, the increase was small and was not considered to be toxicologically significant. In conclusion, none of the animals in any of the glycine-treated groups showed changes that were considered toxicologically significant. Therefore, the no-observed-adverse-effect level of glycine was estimated to be at least 2000 mg/kg/day under the conditions of this study. PMID:24526813

  9. A 4-week Repeated Dose Toxicity Study of Glycine in Rats by Gavage Administration.

    PubMed

    Shibui, Yusuke; Miwa, Tadashi; Yamashita, Mayumi; Chin, Keigi; Kodama, Terutaka

    2013-12-01

    In order to examine the toxicity profile of glycine, an authorized food additive, a solution of glycine in water for injection was administered orally (via gavage) to male SD rats (Crl:CD(SD)) once daily for 4 weeks at doses of 500, 1000 and 2000 mg/kg/day in a volume of 10 mL/kg. Control animals received vehicle only. No animals died, and no glycine-related changes were observed in body weight, food consumption, water consumption, hematology, organ weight, gross pathological examination or histopathological examination. In urinalysis, daily urinary volume and urinary Cl excretion were significantly higher in the 2000 mg/kg/day dose group, and urine pH and urinary protein showed lower trends in the glycine-treated groups. However, these changes were considered to be of little toxicological significance, because there were no histopathological changes in the kidneys or urinary bladder and no changes in other urinary parameters. As regards blood chemistry, phospholipids were significantly higher in the 2000 mg/kg/day dose group. However, the increase was small and was not considered to be toxicologically significant. In conclusion, none of the animals in any of the glycine-treated groups showed changes that were considered toxicologically significant. Therefore, the no-observed-adverse-effect level of glycine was estimated to be at least 2000 mg/kg/day under the conditions of this study. PMID:24526813

  10. Multidose pharmacokineetecs of orally administered florfenicol in channel catfish Ictalurus punctatus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plasma disposition of florfenicol in channel catfish was investigated after an oral dose (10mg/kg for 10 days) administered in freshwater at water temperatures ranging from 24.7 to 25.9°C. Florfenicol concentrations in plasma were analyzed by means of liquid chromatography with MS/MS detection. Af...

  11. The effect of zinc supplementation on the urinary excretion of elements in female athletes.

    PubMed

    Eskici, Gunay; Gunay, Mehmet; Baltaci, Abdulkerim Kasim; Mogulkoc, Rasim

    2016-01-01

    This study was carried out to find out how oral zinc supplementation to elite athletes affects the element changes in the urine. The study registered 10 female athletes who were on the women's volleyball team of Gazi University Sports Club and whose mean age, weight, and height were 14.2±0.42 years, 59.8±7.79kg and 173.6±6.15 cm. The study protocol was approved by the local ethics committee. The athletes who continued their daily routine training sessions (6 days/week) were supplemented with 220mg/day oral zinc sulfate for 4 weeks. In order to induce exhaustion, the subjects were put to a 20-meter shuttle run test before and after supplementation. A total, 7 times urine samples were collected follows as pre and post exercise before the start of the experiment and at the end (4 times), at the end of first, second and third week (3 times). Urinary levels of magnesium, phosphorus, and calcium (mg/dl), as well as zinc, copper, and selenium (μg/dl) were analyzed in the atomic emission device (ICP-MS). Arithmetic means and standard errors of the data were calculated. Kruskal Wallis test was used to determine differences between weeks. Values for which p<0,05 were considered significant. When compared to resting values, urinary excretion of copper and selenium decreased in exercise (p<0,05), but increased with zinc supplementation (p<0,05). Pre- and post-supplementation exercise resulted in reduced urinary zinc excretion (p<0,05). Zinc supplementation increased urinary zinc excretion in one-week intervals over the course of 4 weeks (p<0,05), and reduced selenium levels (p<0,05). When zinc is supplemented to athletes, the relation between the duration and dose of supplementation is important. The results of the study indicated that zinc does not have any negative effect on the urinary excretion of the concerned elements. It can thus be concluded that athletes may benefit from zinc support. PMID:26826808

  12. Urinary Albumin Excretion and Vascular Function in Rheumatoid Arthritis

    PubMed Central

    2016-01-01

    Rheumatoid arthritis (RA) is associated with significant cardiovascular (CV) morbidity and mortality. Increased urinary albumin excretion is a marker of CV risk. There are only few data on urinary albumin excretion in RA patients. Aim of the present study was to investigate urinary albumin excretion in RA patients and analyze, whether there is an association between urinary albumin excretion and vascular function as measured by the augmentation index (AIx). In a total of 341 participants (215 with RA, 126 without RA) urinary albumin-creatinine ratio (ACR) was determined and the AIx was measured. The Kolmogorov-Smirnov-test was used to cluster patient groups whose distributions of ACR can be considered to be equal. A crude analysis showed a median ACR of 6.6 mg/g in the RA group and 5.7 mg/g in patients without RA (P > 0.05). In order to account for diabetes (DM) we formed 4 distinct patient groups. Group 1: RA-/DM- (n = 74); group 2: RA+/DM- (n = 195); group 3: RA-/DM+ (n = 52); group 4: RA+/DM+ (n = 20). Clustering of these groups revealed two distinct patient groups: those without RA and DM, and those with either RA or DM or both. The latter group showed statistically significant higher ACR (median 8.1 mg/g) as the former (median 4.5 mg/g). We found no significant correlation between AIx and ACR. Urinary albumin excretion in patients with RA or DM or both is higher than in subjects without RA and DM. This can be seen as a sign of vascular alteration and increased CV risk in these patients. PMID:26955238

  13. Elevated urinary excretion of aluminium and iron in multiple sclerosis.

    PubMed

    Exley, Christopher; Mamutse, Godwin; Korchazhkina, Olga; Pye, Eleanor; Strekopytov, Stanislav; Polwart, Anthony; Hawkins, Clive

    2006-10-01

    Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease of the central nervous system of as yet unknown aetiology. A consensus of opinion has suggested that the disorder is the result of an interplay between environmental factors and susceptibility genes. We have used a battery of analytical techniques to determine if the urinary excretion of i) markers of oxidative damage; ii) iron and iii) the environmental toxin aluminium and its antagonist, silicon, are altered in relapsing-remitting (RRMS) and secondary progressive MS (SPMS). Urinary concentrations of oxidative biomarkers, MDA and TBARS, were not found to be useful indicators of inflammatory disease in MS. However, urinary concentrations of another potential marker for inflammation and oxidative stress, iron, were significantly increased in SPMS (P<0.01) and insignificantly increased in RRMS (P>0.05). Urinary concentrations of aluminium were also significantly increased in RRMS (P<0.001) and SPMS (P <0.05) such that the levels of aluminium excretion in the former were similar to those observed in individuals undergoing metal chelation therapy. The excretion of silicon was lower in MS and significantly so in SPMS (P<0.05). Increased excretion of iron in urine supported a role for iron dysmetabolism in MS. Levels of urinary aluminium excretion similar to those seen in aluminium intoxication suggested that aluminium may be a hitherto unrecognized environmental factor associated with the aetiology of MS. If aluminium is involved in MS then an increased dietary intake of its natural antagonist, silicon, might be a therapeutic option. PMID:17086897

  14. Decreased excretion of glycosaminoglycans in patients with primary glomerular diseases.

    PubMed

    Tencer, J; Torffvit, O; Björnsson, S; Thysell, H; Grubb, A; Rippe, B

    1997-10-01

    Urine glycosaminoglycans (GAG) concentrations were measured in 150 patients with primary glomerulonephritides: endocapillary glomerulonephritis, mesangial proliferative glomerulonephritis, IgA nephropathy, membranous glomerulonephritis and minimal change nephropathy, and in 63 healthy controls and 19 patients with diabetes nephropathy. The urine GAG to creatinine ratios (GCR) were significantly reduced (p < 0.01) in all the glomerulonephritides investigated (0.20 mg/mmol in endocapillary glomerulonephritis, 1.60 mg/mmol in mesangial proliferative glomerulonephritis, 1.74 mg/mmol in IgA nephropathy, 1.09 mg/mmol in membranous nephropathy, and 1.16 mg/mmol in minimal change nephropathy) compared to healthy controls (2.87 mg/mmol) but not compared to diabetes patients (1.17 mg/mmol). Also, the GCR in a group of 23 non-albuminuric glomerulonephritis patients (1.98 mg/mmol) was shown to be significantly decreased (p < 0.01) compared to healthy controls. Moreover, the GCR was significantly lower (p < 0.01) in endocapillary glomerulonephritis than in any of the other diseases studied. The GAG excretion per functioning glomerular area, calculated as fractional GAG excretion (FGE), was decreased in all the glomerulonephritides investigated compared to both healthy controls and diabetes nephropathy. The decreased GAG excretion in glomerulonephritides, obtained in the present study, might be a consequence of decreased synthesis or turnover of GAG in the functioning nephrons whereas the mechanisms for the reduced GAG excretion in diabetes nephropathy might be of a different nature. Urinary GAG excretion in this group of glomerular disorders and particularly in endocapillary glomerulonephritis, may lead to new approaches in non-invasive renal diagnostics and, particularly with regard to the differentiation of acute and chronic forms of glomerulonephritides. PMID:9352154

  15. Urinary Albumin Excretion and Vascular Function in Rheumatoid Arthritis.

    PubMed

    Pieringer, Herwig; Brummaier, Tobias; Piringer, Bettina; Auer-Hackenberg, Lorenz; Hartl, Andreas; Puchner, Rudolf; Pohanka, Erich; Schmid, Michael

    2016-03-01

    Rheumatoid arthritis (RA) is associated with significant cardiovascular (CV) morbidity and mortality. Increased urinary albumin excretion is a marker of CV risk. There are only few data on urinary albumin excretion in RA patients. Aim of the present study was to investigate urinary albumin excretion in RA patients and analyze, whether there is an association between urinary albumin excretion and vascular function as measured by the augmentation index (AIx). In a total of 341 participants (215 with RA, 126 without RA) urinary albumin-creatinine ratio (ACR) was determined and the AIx was measured. The Kolmogorov-Smirnov-test was used to cluster patient groups whose distributions of ACR can be considered to be equal. A crude analysis showed a median ACR of 6.6 mg/g in the RA group and 5.7 mg/g in patients without RA (P > 0.05). In order to account for diabetes (DM) we formed 4 distinct patient groups. Group 1: RA-/DM- (n = 74); group 2: RA+/DM- (n = 195); group 3: RA-/DM+ (n = 52); group 4: RA+/DM+ (n = 20). Clustering of these groups revealed two distinct patient groups: those without RA and DM, and those with either RA or DM or both. The latter group showed statistically significant higher ACR (median 8.1 mg/g) as the former (median 4.5 mg/g). We found no significant correlation between AIx and ACR. Urinary albumin excretion in patients with RA or DM or both is higher than in subjects without RA and DM. This can be seen as a sign of vascular alteration and increased CV risk in these patients. PMID:26955238

  16. Increased Renal Solute Excretion in Rats Following Space Flight

    NASA Technical Reports Server (NTRS)

    Wade, Charles E.; Moore, A. L.; Morey-Holton, E.

    1995-01-01

    Following space flight a diuresis, due to an increase in free water clearance, has been suggested in humans. To assess the effects of space flight on renal function, rats were flown in space for 14 days. Rats were divided into three groups; vivarium controls (V;n=6; housed 2/shoe box cage), flight controls (FC;n=6; group housed in a flight cage), and flight animals (F;n=6). Upon landing all animals were placed into individual metabolic cages. Urine was collected daily for 7 days and every other day for 14 days. Urine output was increased (p less than 0.05; ANOVA) following flight for 3 days. On postflight day 1, flow rates were, V=6.8 plus or minus 0.9, FC=8.711.8 and F=16.6 plus or minus 2.7 microliter/min. Excretion rates of Na+ and K+ were increased, resulting in an increased osmotic excretion rate (V=7.9 plus or minus 0.9, FC=6.1 plus or minus 0.7 and F=13.5 plus or minus 0.7 uOsm/min). Creatinine excretion rate was increased over the first two postflight days. In the absence of changes in plasma creatinine, Na+, or K+ (samples obtained immediately post flight from similar rats compared to Day 14), GFR was increased following space flight. The increased excretion of solute was thus the result of increased delivery and decreased reabsorption. Osmotic clearance was increased (V=28, FC=27 and F=51 microliter/min), while free water clearance was decreased post flight (V=-21,FC=-18 and F=-34 microliter/min). In rats, the postflight diuresis is the result of an increase in solute (osmotic) excretion with an accompanying reduction in free water clearance.

  17. Impairment of renal sodium excretion in tropical residents - phenomenological analysis

    NASA Astrophysics Data System (ADS)

    Arthur, S. K.; Aryee, P. A.; Amuasi, J.; Hesse, I. F. A.; Affram, R. K.

    There is evidence of impaired renal sodium excretion in salt-sensitive African Blacks. A decreased rate of renal sodium chloride (NaCl) excretion, low plasma renin activity and a tendency to elevated blood pressure are the hallmarks of salt sensitivity. Recent evidence indicates that increased proximal and distal tubular fluid reabsorption in some tropical residents may explain the impaired sodium excretion in these people. In this study of a cohort population, we speculated that subjects selected from that population might be salt-sensitive. We therefore measured the sodium balance in 10 normotensive male subjects over 10 consecutive days, after they had ingested a normal or a high amount of sodium, as NaCl (salt) in their diet. We quantified their renal sodium excretion rate by phenomenological analysis of their sodium balance data. We also measured plasma renin activity for 7 consecutive days in a separate group of 6 male and 4 female subjects in order to assess the state of their renin/angiotensin system. We selected all our subjects from a cohort population of 269 subjects randomly selected from a community known to have a high prevalence of primary hypertension. Our data on two separate groups of subjects from the same cohort population revealed delayed renal sodium excretion with t1/2 of about 5 days, compared to published data for normal individuals with t1/2 of less than 24 h. Also, plasma renin activity levels were low. Hence, our subjects are salt-sensitive. Quantification of their renal impairment is important for various reasons: it heightens one's appreciation of the problem of salt retention in African Blacks who are salt-sensitive and it also underlines the importance of the need for further research into the benefits of dietary salt restriction for reducing cardiovascular mortality in African populations, as has been done in some Western countries.

  18. Amorphous Silica Based Nanomedicine with Safe Carrier Excretion and Enhanced Drug Efficacy

    NASA Astrophysics Data System (ADS)

    Zhang, Silu

    switch, led to not only high but also stable drug concentration in cytosol within a sustained period. This resulted in enhanced drug efficacy, which is especially manifested in multidrug resistant (MDR) cancer cells, due to the fact that the NP-carrier drug can efficiently bypass the efflux mechanisms and increase drug availability. Together with its feature of spontaneous carrier decomposition and safe excretion, this type of nanomedicine's high drug efficacy highlights its potential for low dose anticancer drug treatment and reduced adverse effect to biological system, holding great promise for clinical translation. The enhanced drug efficacy by employing the self-decomposable silica nanocarrier is also demonstrated in photodynamic therapy (PDT). The loose and fragmentable features of the self-decomposable SiO2-photosensitizer (PS) NPs promoted the outdiffusion of the generated ROS, which resulted in a higher efficacy than that of dense SiO2-PS NPs. On the other hand, we also explored another nanocarrier configuration of Au nanorods decorated SiO2 NP, with PS drug embedded into dense SiO2 matrix. A different mechanism of drug efficacy enhancement was presented as the Au's surface plasmon resonance enhanced the ROS production. Although the drug efficacy of such SiO2(PS)-Au NPs was similar to that of self-decomposable SiO2-PS NPs, their potential for clinical applications was limited without the feature of safe carrier excretion. In summary, the self-decomposable SiO2 based NP developed is a most promising system to serve as safe and effective carriers for drugs. Together with the known biocompatibility of silica, the feature of controllable drug release and simultaneous carrier decomposition achieved in the self-decomposable SiO2-drug NPs make it ideal for a wide range of therapeutic applications.

  19. The biodistribution and dosimetry of {sup 117m}Sn DTPA with special emphasis on active marrow absorbed doses

    SciTech Connect

    Stubbs, J.; Atkins, H.

    1999-01-01

    {sup 117m}Sn(4+) DTPA is a new radiopharmaceutical for the palliation of pain associated with metastatic bone cancer. Recently, the Phase 2 clinical trials involving 47 patients were completed. These patients received administered activities in the range 6.7--10.6 MBq/kg of body mass. Frequent collections of urine were acquired over the first several hours postadministration and daily cumulative collections were obtained for the next 4--10 days. Anterior/posterior gamma camera images were obtained frequently over the initial 10 days. Radiation dose estimates were calculated for 8 of these patients. Each patient`s biodistribution data were mathematically simulated using a multicompartmental model. The model consisted of the following compartments: central, bone, kidney, other tissues, and cumulative urine. The measured cumulative urine data were used as references for the cumulative urine excretion compartment. The total-body compartment (sum of the bone surfaces, central, kidney, and other tissues compartments) was reference to all activity not excreted in the urine.

  20. Dietary fibers reduce the urinary excretion of 1-hydroxypyrene following intravenous administration of pyrene.

    PubMed

    Viau, C; Zaoui, C; Charbonneau, S

    2004-03-01

    During biological monitoring of exposure to a chemical, a possible source of interindividual variability in the measurement of a urinary metabolite that undergoes enterohepatic cycling is the presence of dietary fiber in the gastrointestinal tract. This study examined the effect of diets containing either the insoluble fiber Alphacel (nonnutritive bulk cellulose) or the soluble pectin (from citrus fruit, MW 20,000-40,000). Five groups of male Sprague-Dawley rats received one of the following diets: poor (5% w/w) or rich (15% w/w) in Alphacel, poor (5% w/w) or rich (15% w/w) in pectin, or no fiber (NF). Five micromol/kg of pyrene was administered by iv injection immediately after feeding the animals with their respective diet, and urine and feces collections started for the determination of 1-hydroxypyrene (1-OHP), a metabolite of pyrene. The type of fiber had no influence on the results. The rats receiving diets both poor and rich in fiber excreted less 1-OHP (18 +/- 8 and 15 +/- 7 pmol per g of rat, respectively) in the 24-h urine samples than the NF group (28 +/- 6 pmol/g). There was a nonstatistically significant trend towards increased fecal and total (urinary + fecal) 1-OHP excretion with increasing amount of fiber in the diet. An in vitro experiment showed an inverse correlation (r(2) = 0.98) between the amount of Alphacel in suspension in a 1-OHP aqueous solution and the recovery of 1-OHP from the soluble fraction. The reduction in urinary output of the metabolite due to fiber reaching approximately 40% may contribute to its interindividual variability observed in occupational and environmental studies. PMID:14691205

  1. Intake and urinary excretion of sodium chloride under varying conditions of effort and environment heat

    NASA Technical Reports Server (NTRS)

    Zohar, E.; Adar, R.; Tennenbaum, J.; Kesten, M.

    1982-01-01

    Intake and urinary excretion of sodium were investigated in a group of young, healthy and acclimated men. The sodium excretions of workers and of machinists in the engine rooms of a ship were also investigated.

  2. Excretion of stable isotopes in man: A valuable source of information on trace metal kinetics

    SciTech Connect

    Fennessey, P.V.; Miller, L.V.; Westcott, J.E.; Kindstrand, L.; Hambidge, K.M. )

    1991-03-15

    The analysis of individual fecal samples collected for at least ten days following an oral dose of {sup 70}Zn provides data on transit time, absorption and the excretion of isotope that has been absorbed and then secreted back into the lumen of the intestine. The analysis of data from more than 80 human studies where enriched Zn stable isotopes were given orally has provided a valuable data base on Zn kinetics. A plot of enrichment in the fecal samples as a function of time reveals the average time of maximum appearance as well as the time limit needed for elimination of unabsorbed isotope. A plot of cumulative enrichment as a function of time reveals information on both absorption and secretion rate of absorbed isotope. This data base provides investigators with new information that they can use to optimize their data collection schemes and serves as a model for the study of other trace metals.

  3. Excretion of 14C-edrophonium and its metabolites in bile

    PubMed Central

    Back, D. J.; Calvey, T. N.

    1972-01-01

    1. The metabolism and biliary excretion of 14C-edrophonium chloride was studied in Wistar rat. 2. Approximately 5% of the dose was recovered from bile in 6 hours. Most of the radioactivity was eliminated as 14C-edrophonium glucuronide. Small amounts of the unchanged drug were also detected in bile, particularly during the first hour after administration of the drug. 3. The concentration of 14C-edrophonium glucuronide in bile was approximately 15-20 times its concentration in plasma. 4. In contrast, the concentration of unchanged 14C-edrophonium was similar in bile and plasma. 5. Evidence is presented that unchanged 14C-edrophonium is transferred from plasma to bile via the peribiliary vascular plexus. PMID:5040663

  4. Single-dose pharmacokinetics of indinavir and the effect of food.

    PubMed

    Yeh, K C; Deutsch, P J; Haddix, H; Hesney, M; Hoagland, V; Ju, W D; Justice, S J; Osborne, B; Sterrett, A T; Stone, J A; Woolf, E; Waldman, S

    1998-02-01

    Indinavir sulfate is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor indicated for treatment of HIV infection and AIDS in adults. The purpose of this report is to summarize single-dose studies which characterized the pharmacokinetics of the drug and the effect of food in healthy volunteers. Indinavir concentrations in plasma and urine were obtained by high-pressure liquid chromatography and UV detection assay methods. The results indicate that indinavir was rapidly absorbed in the fasting state, with the time to the maximum concentration in plasma occurring at approximately 0.8 h for all doses studied. Over the 40- to 1,000-mg dose range studied, concentrations in plasma and urinary excretion of unchanged drug increased greater than dose proportionally. The nonlinear pharmacokinetics were attributed to the dose-dependent oxidative metabolism of first-pass metabolism as well as to metabolism in the systemic circulation. Renal clearance slightly exceeded the glomerular filtration rate, suggesting a net tubular secretion component. At high concentrations in plasma, tubular secretion appeared to be lowered because there was a trend for a decreased renal clearance. Administration of 400 mg of indinavir sulfate following a high-fat breakfast resulted in a blunted and decreased absorption (areas under the concentration-time curves [AUCs], 6.86 microM.h in the fasted state versus 1.54 microM.h in the fed state; n = 10). However, two types of low-fat meals were found to have no significant effect on the absorption of 800 mg of indinavir sulfate (AUCs, 23.15 microM.h in the fasted state versus 22.71 and 21.36 microM.h, respectively, in the fed state; n = 11). Immediately following dosing, the concentrations of indinavir in urine often exceeded its intrinsic solubility. To reduce the risk of nephrolithiasis, it is recommended that indinavir sulfate be administered with water. PMID:9527781

  5. The effect of surgery on the renal excretion of beta 2-microglobulin.

    PubMed

    Walenkamp, G H; Vree, T B; Guelen, P J; Jongman-Nix, B

    1983-03-28

    Surgical trauma causes an increase in the renal excretion rate of beta 2-microglobulin whilst creatinine excretion is not influenced. The increase in the renal excretion rate of beta 2-microglobulin is probably the result of an increased release of beta 2-microglobulin by the cells which exceeds a maximum in the active tubular reabsorption of the compound by the proximal tubule cell. The renal excretion of beta 2-microglobulin is proportional to the relative clinical trauma score. PMID:6189646

  6. Pharmacokinetics, bioavailability, metabolism and excretion of δ-viniferin in rats

    PubMed Central

    Mao, Ping; Lei, Yinping; Zhang, Tingting; Ma, Chen; Jin, Bo; Li, Tong

    2016-01-01

    A highly rapid and sensitive liquid chromatographic–electrospray ionization tandem mass spectrometric (LC–ESI-MS/MS) method was developed and validated for the determination of trans-δ-viniferin (Rs-1) in rat plasma, urine and feces. All biological samples were prepared by liquid–liquid extraction and hesperetin was included as an internal standard (IS). Chromatographic separation was achieved on a shim-pack XR-ODS column using a gradient mobile phase. MS/MS detection was performed by negative ion electrospray ionization. The method was sensitive with a lower limit of quantification of 1.42 ng/mL and linear over the range of 1.42–2172 ng/mL in all matrices. The method was applied to study the pharmacokinetics, bioavailability, metabolism, and excretion of Rs-1 in rats following a single oral or intravenous dose. Two metabolites, Rs-1 glucuronide and Rs-1 sulfate, were detected in plasma and in urine after administration of Rs-1. The absolute oral bioavailability of Rs-1 was 2.3%, and the total absorption rose to 31.5% with addition of its glucuronide and sulfate metabolites. Only 0.09% of the gavaged dose, including Rs-1 and metabolites, was excreted in the urine, while 60.3% was found in the feces in unchanged form. The results indicate that both poor absorption and extensive metabolism were the important factors that led to the poor bioavailability of Rs-1, which can provide a basis for further studies on structural modification and dosage form design. PMID:27175336

  7. Ocular toxicity from systemically administered xenobiotics

    PubMed Central

    Gokulgandhi, Mitan R; Vadlapudi, Aswani Dutt; Mitra, Ashim K

    2015-01-01

    Introduction The eye is considered as the most privileged organ because of the blood–ocular barrier that acts as a barrier to systemically administered xenobiotics. However, there has been a significant increase in the number of reports on systemic drug-induced ocular complications. If such complications are left untreated, then it may cause permanent damage to vision. Hence, knowledge of most recent updates on ever-increasing reports of such toxicities has become imperative to develop better therapy while minimizing toxicities. Areas covered The article is mainly divided into anterior and posterior segment manifestations caused by systemically administered drugs. The anterior segment is further elaborated on corneal complications where as the posterior segment is focused on optic nerve, retinal and vitreous complications. Furthermore, this article includes recent updates on acute and chronic ocular predicaments, in addition to discussing various associated symptoms caused by drugs. Expert opinion Direct correlation of ocular toxicities due to systemic drug therapy is evident from current literature. Therefore, it is necessary to have detailed documentation of these complications to improve understanding and predict toxicities. We made an attempt to ensure that the reader is aware of the characteristic ocular complications, the potential for irreversible drug toxicity and indications for cessation. PMID:22803583

  8. Fecal excretion of Bifidobacterium infantis 35624 and changes in fecal microbiota after eight weeks of oral supplementation with encapsulated probiotic

    PubMed Central

    Charbonneau, Duane; Gibb, Roger D.; Quigley, Eamonn M.M.

    2013-01-01

    Certain randomized, placebo-controlled trials of oral supplementation with B. infantis 35624 have demonstrated the amelioration of symptoms of irritable bowel syndrome. Potential GI colonization by B. infantis 35624 or effects of supplementation on resident GI microbiota may pertain to these clinical observations. In this study, fecal excretion of B. infantis 35624 before, during and after 8 weeks of daily treatment was compared in subjects with IBS who received either the encapsulated oral supplement (n = 39) or placebo (n = 37) and in healthy subjects who received the supplement (n = 41). Secondarily, changes in assessed fecal microbiota and IBS symptoms were determined. Supplementation significantly increased fecal B. infantis 35624 excretion vs. placebo in IBS subjects; excretion in healthy subjects receiving supplement was quantitatively similar. Fecal levels of the probiotic declined and approached baseline once dosing ceased, documenting that colonization is transient. Although supplementation increased numbers of B infantis 35624 within the GI tract, limited changes in 10 other fecal taxa were observed either in healthy subjects or those with IBS. No impact on IBS symptoms was observed. Detection of bacterial DNA in fecal samples suggests that the probiotic is able to survive transit through the GI tract, although strain selective culture techniques were not performed to confirm viability of B. infantis 35624 in the feces. Continuous probiotic administration was necessary to maintain steady-state transit. Given the complex spectrum of GI microbiota, however, monitoring perturbations in selected taxa may not be not a useful indicator of probiotic function. PMID:23549409

  9. Blood Clearance, Distribution, Transformation, Excretion, and Toxicity of Near-Infrared Quantum Dots Ag2Se in Mice.

    PubMed

    Tang, Huan; Yang, Sheng-Tao; Yang, Yi-Fan; Ke, Da-Ming; Liu, Jia-Hui; Chen, Xing; Wang, Haifang; Liu, Yuanfang

    2016-07-20

    As a novel fluorescent probe in the second near-infrared window, Ag2Se quantum dots (QDs) exhibit great prospect in in vivo imaging due to their maximal penetration depth and negligible background. However, the in vivo behavior and toxicity of Ag2Se QDs still largely remain unknown, which severely hinders their wide-ranging biomedical applications. Herein, we systematically studied the blood clearance, distribution, transformation, excretion, and toxicity of polyethylene glycol (PEG) coated Ag2Se QDs in mice after intravenous administration with a high dose of 8 μmol/kg body weight. QDs are quickly cleared from the blood with a circulation half-life of 0.4 h. QDs mainly accumulate in liver and spleen and are remarkably transformed into Ag and Se within 1 week. Ag is excreted from the body readily through both feces and urine, whereas Se is excreted hardly. The toxicological evaluations demonstrate that there is no overt acute toxicity of Ag2Se QDs to mice. Moreover, in regard to the in vivo stability problem of Ag2Se QDs, the biotransformation and its related metabolism are intensively discussed, and some promising coating means for Ag2Se QDs to avert transformation are proposed as well. Our work lays a solid foundation for safe applications of Ag2Se QDs in bioimaging in the future. PMID:27351208

  10. Uric acid excretion predicts increased aggression in urban adolescents.

    PubMed

    Mrug, Sylvie; Mrug, Michal

    2016-09-01

    Elevated levels of uric acid have been linked with impulsive and disinhibited behavior in clinical and community populations of adults, but no studies have examined uric acid in relation to adolescent aggression. This study examined the prospective role of uric acid in aggressive behavior among urban, low income adolescents, and whether this relationship varies by gender. A total of 84 adolescents (M age 13.36years; 50% male; 95% African American) self-reported on their physical aggression at baseline and 1.5years later. At baseline, the youth also completed a 12-h (overnight) urine collection at home which was used to measure uric acid excretion. After adjusting for baseline aggression and age, greater uric acid excretion predicted more frequent aggressive behavior at follow up, with no significant gender differences. The results suggest that lowering uric acid levels may help reduce youth aggression. PMID:27180134

  11. Metabolism and excretion of [14C] verruculogen in a sheep.

    PubMed

    Perera, K P; Mantle, P G; Penny, R H

    1982-05-01

    [14C] Verruculogen (75 micrograms/kg) was given intravenously to a sheep under barbiturate anaesthesia to prevent the severe tremor and convulsions which would otherwise have occurred. Two hours later 28 per cent of the tremorgenic mycotoxin was detected in the liver, bile and small intestine. Approximately 0.5 per cent was excreted in the urine. Trace amounts of radiolabel were detected in the cortex and corpus striatum of the brain. Verruculogen was metabolised by the liver and converted completely to four more polar products, including two isomeric forms of desoxy-verruculogen and the weakly tremorgenic mycotoxin TR-2. The principal and most polar metabolite excreted is probably an isomer of TR-2. PMID:7100651

  12. Blood pressure, sodium intake, insulin resistance, and urinary nitrate excretion.

    PubMed

    Facchini, F S; DoNascimento, C; Reaven, G M; Yip, J W; Ni, X P; Humphreys, M H

    1999-04-01

    The objective of this study was to investigate the relationships among various humoral factors thought to be involved in the regulation of blood pressure during high NaCl intake. Nineteen healthy subjects underwent sequential 5-day periods ingesting a low-sodium (25 mmol/d) or high-sodium (200 mmol/d) diet. Insulin resistance was assessed by the steady-state plasma glucose concentration at the end of a 3-hour insulin suppression test. Insulin resistance correlated inversely with natriuresis (P=0.04) and directly with increase in weight (P=0.03). The increase in mean arterial pressure associated with the high-sodium diet correlated directly with the gain in weight (P<0.05) and inversely with the increase in urinary nitrate excretion (P<0.0001). In a multiple regression model, more than 2/3 of the variance in mean arterial pressure was accounted for by the gain in weight and change in urinary nitrate excretion. The steady-state plasma glucose concentrations obtained with the 2 diets were similar, indicating that insulin resistance was unaffected by sodium intake. During high sodium intake, plasma renin activity and aldosterone decreased and plasma atrial natriuretic peptide increased; these changes did not correlate with the change in mean arterial pressure, insulin resistance, or change in urinary nitrate excretion. To the extent that urinary nitrate excretion reflects activity of the endogenous nitric oxide system, these results suggest that the salt sensitivity of mean arterial pressure may be related to blunted generation of endogenous nitric oxide. The results also demonstrate that insulin-resistant individuals have an impaired natriuretic response to high sodium intake. PMID:10205239

  13. Factors affecting urinary excretion of testosterone metabolites conjugated with cysteine.

    PubMed

    Fabregat, Andreu; Marcos, Josep; Segura, Jordi; Ventura, Rosa; Pozo, Oscar J

    2016-01-01

    The implementation of the athlete steroidal passport in doping control analysis aims to detect intra-individual changes in the steroid profile related to the abuse of anabolic steroids. In this context, the study of intrinsic variations associated with each marker is of utmost importance. In the present work, the influence of several factors in the excretion of the recently reported testosterone metabolites conjugated with cysteine (Δ(1) -AED; 1,4-androstadien-3,17-dione, Δ(6) -AED; 4,6-androstadien-3,17-dione, Δ(6) -T; 4,6-androstadien-17β-ol-3-one, and Δ(15) -AD; 15-androsten-3,17-dione) is evaluated for the first time. Degradation experiments at 37 °C proved that, although the cysteinyl moiety is released, the variation for urinary Δ(1) -AED/Δ(6) -AED, Δ(1) -AED/Δ(6) -T ratios is less than 30%. Moreover, freeze/thaw cycle testing resulted in RSDs values below 15% for all the analytes. Regarding infradian variability, moderate variations (below 40%) were observed. Additionally, notable alterations in the excretion of these compounds have been observed in the earliest stages of pregnancy. UGT2B17 polymorphism, responsible for the low T/E ratio found in some population, does not influence the excretion of cysteinyl compounds whereas the intake of exogenous substances (alcohol or 5α-reductase inhibitors) dramatically affects their excretion. The urinary concentrations of Δ(1) -AED, Δ(6) -AED, and Δ(15) -AD decreased (<50 %) after the ethanol intake, whereas after the administration of dutasteride, an important increase was observed for the concentrations of Δ(6) -AED, Δ(6) -T and Δ(15) -AD. Overall, the presented data describes the stability of the urinary cysteinyl steroids under the influence of many factors, proving their potential as suitable parameters to be included in the steroidal module of the athlete's biological passport. PMID:25917157

  14. Competitive inhibition of SGLT2 by tofogliflozin or phlorizin induces urinary glucose excretion through extending splay in cynomolgus monkeys.

    PubMed

    Nagata, Takumi; Suzuki, Masayuki; Fukazawa, Masanori; Honda, Kiyofumi; Yamane, Mizuki; Yoshida, Ayae; Azabu, Hiroko; Kitamura, Hidekazu; Toyota, Naoto; Suzuki, Yoshiyuki; Kawabe, Yoshiki

    2014-06-15

    Sodium-glucose cotransporter 2 (SGLT2) inhibitors showed a glucose lowering effect in type 2 diabetes patients through inducing renal glucose excretion. Detailed analysis of the mechanism of the glucosuric effect of SGLT2 inhibition, however, has been hampered by limitations of clinical study. Here, we investigated the mechanism of urinary glucose excretion using nonhuman primates with SGLT inhibitors tofogliflozin and phlorizin, both in vitro and in vivo. In cells overexpressing cynomolgus monkey SGLT2 (cSGLT2), both tofogliflozin and phlorizin competitively inhibited uptake of the substrate (α-methyl-d-glucopyranoside; AMG). Tofogliflozin was found to be a selective cSGLT2 inhibitor, inhibiting cSGLT2 more strongly than did phlorizin, with selectivity toward cSGLT2 1,000 times that toward cSGLT1; phlorizin was found to be a nonselective cSGLT1/2 inhibitor. In a glucose titration study in cynomolgus monkeys under conditions of controlled plasma drug concentration, both tofogliflozin and phlorizin increased fractional excretion of glucose (FEG) by up to 50% under hyperglycemic conditions. By fitting the titration curve using a newly introduced method that avoids variability in estimating the threshold of renal glucose excretion, we found that tofogliflozin and phlorizin lowered the threshold and extended the splay in a dose-dependent manner without significantly affecting the tubular transport maximum for glucose (TmG). Our results demonstrate the contribution of SGLT2 to renal glucose reabsorption (RGR) in cynomolgus monkeys and demonstrate that competitive inhibition of cSGLT2 exerts a glucosuric effect by mainly extending splay and lowering threshold without affecting TmG. PMID:24761001

  15. Nitrogen balance and mineral excretion in growing male pigs injected with a human growth hormone-releasing factor analog.

    PubMed Central

    Dubreuil, P; Abribat, T; Brazeau, P; Lapierre, H

    1998-01-01

    A human growth hormone-releasing factor analog ([Desamino-Tyr1,D-Ala2,Ala15] hGRF(1-29) NH2) has been reported to reduce feed intake and increase growth and feed efficiency in a dose-dependent manner in growing pigs. The aim of this study was to determine the effect of this analog on nitrogen (N) balance and mineral excretion. Fifteen castrated male Yorkshire x Landrace pigs (45.9 +/- 1.4 kg) were randomly allotted to 2 groups: control (saline, n = 7) and GRF (6.66 micrograms/kg sc, TID, n = 8). The animals were injected for 20 consecutive days: feces and urine were collected during the last 10 d of injection. The animals had free access to water and food until satiety (approximately 15 min) at 07:00, 11:00, 15:00, 19:00, 23:00 and 07:00 h. The diet consisted of a hog fattening ration (18.0% crude protein). Blood samples were collected on the last day of the study by venipuncture. This analog increased (P < 0.05) insulin-like growth factor-1 and glucose serum concentrations and decreased (P < 0.05) serum urea nitrogen concentration and feed intake. The GRF-treated animals ingested less N, excreted less N in urine and feces to retain a similar amount of N than controls. The apparent coefficient of digestibility of the N has been slightly increased (P < 0.05) by GRF. Urinary excretion of P, K, and Cl decreased (P < 0.01) with GRF treatment. In conclusion, this GRF analog increased N digestibility and retention relative to N ingestion and reduced urinary N, P, K, and Cl excretion. PMID:9442933

  16. Airborne arsenic exposure and excretion of methylated arsenic compounds.

    PubMed Central

    Smith, T J; Crecelius, E A; Reading, J C

    1977-01-01

    First void urine samples were collected from copper smelter workers exposed to inorganic arsenic and from unexposed controls. Arsenic compounds (As (III), As (V), methylarsonic acid and dimethylarsinic acid) in these samples were analyzed by selective volatilization as arsines with determination of arsenic by plasma excitation emission spectrometry. On the day preceding the urine sample collection a breathing zone measurement was made of respirable arsenic particulates for each subject. It was found that all of the subjects, including the controls excreted arsenic primarily as methylated species. Approximately 50% of the total arsenic was excreted as dimethylarsinic acid and 20% as methylarsonic acid. Slight differences in the proportion of various arsenic compounds were observed with varying levels of inorganic arsenic exposure. Amounts of arsenic species were all closely correlated with each other and with exposure. Irrespirable particulate exposures were measured on a subset of high exposure workers. Irrespirable arsenic was found to be more closely correlated with excretion of arsenic compounds than was respirable arsenic. PMID:908318

  17. Biliary and renal excretions of cefpiramide in Eisai hyperbilirubinemic rats.

    PubMed Central

    Muraoka, I; Hasegawa, T; Nadai, M; Wang, L; Haghgoo, S; Tagaya, O; Nabeshima, T

    1995-01-01

    Eisai hyperbilirubinemic mutant rats (EHBRs) with conjugated hyperbilirubinemia were recently derived from Sprague-Dawley rats (SDRs). The pharmacokinetic characteristics of the beta-lactam antibiotic cefpiramide (CPM), which is mainly excreted into bile, were investigated in 10- and 20-week-old EHBRs and were compared with those in 20-week-old healthy SDRs. The pharmacokinetic parameters of CPM after an intravenous administration of 20 mg/kg of body weight were estimated for each rat by noncompartmental methods. When compared with age-matched healthy SDRs, significant decreases (by approximately 30%) in the systemic clearance of CPM were observed in 20-week-old EHBRs. The biliary clearance of CPM in 20-week-old EHBRs markedly decreased to less than 10% of that in age-matched healthy SDRs, while total urinary recovery of unchanged CPM increased to threefold and renal clearance doubled. However, no significant differences in any of the pharmacokinetic parameters of CPM were observed between the two groups of EHBRs. There were no significant differences among the three groups in the steady-state volume of distribution of CPM. The present study indicates that hyperbilirubinemia induces an increase in the urinary excretion ability of CPM in return for a reduction in the biliary excretion. PMID:7695332

  18. Urinary 3-methylhistidine excretion increases with repeated weight training exercise.

    PubMed

    Pivarnik, J M; Hickson, J F; Wolinsky, I

    1989-06-01

    This investigation examines the effect of progressive resistance weight training exercise on urinary 3-methylhistidine (3-MH) excretions in untrained subjects. For 19 consecutive days, 11 males were fed a weight maintenance, lactovegetarian diet which contained the Recommended Dietary Allowance (0.8g.kg-1.d-1) for protein. No exercise was performed for the first 7 d of the study. Subjects were strength tested on day 8 and performed upper and lower body weight training exercises from days 9-19. Complete, 24-h urine collections were obtained from each subject on a daily basis. Samples were assayed for creatinine and 3-MH. Stable baseline 3-MH values were present during the pre-exercise control period. Significant increases in 3-MH occurred by study day 11, which was the third day of weight training exercise. This was true regardless of whether the data were expressed by daily excretions (microM.d-1; P less than 0.01), per unit of body weight (microM.kg-1.d-1; P less than 0.005), or per unit of creatinine excretion (microM.g Creat-1.d-1; P less than 0.001). Since urinary 3-MH is an index of actin and myosin catabolism, these data support the hypothesis that the rate of skeletal muscle degradation is increased during strength building exercises. PMID:2733577

  19. Excreted Cytoplasmic Proteins Contribute to Pathogenicity in Staphylococcus aureus.

    PubMed

    Ebner, Patrick; Rinker, Janina; Nguyen, Minh Thu; Popella, Peter; Nega, Mulugeta; Luqman, Arif; Schittek, Birgit; Di Marco, Moreno; Stevanovic, Stefan; Götz, Friedrich

    2016-06-01

    Excretion of cytoplasmic proteins in pro- and eukaryotes, also referred to as "nonclassical protein export," is a well-known phenomenon. However, comparatively little is known about the role of the excreted proteins in relation to pathogenicity. Here, the impact of two excreted glycolytic enzymes, aldolase (FbaA) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), on pathogenicity was investigated in Staphylococcus aureus Both enzymes bound to certain host matrix proteins and enhanced adherence of the bacterial cells to host cells but caused a decrease in host cell invasion. FbaA and GAPDH also bound to the cell surfaces of staphylococcal cells by interaction with the major autolysin, Atl, that is involved in host cell internalization. Surprisingly, FbaA showed high cytotoxicity to both MonoMac 6 (MM6) and HaCaT cells, while GAPDH was cytotoxic only for MM6 cells. Finally, the contribution of external FbaA and GAPDH to S. aureus pathogenicity was confirmed in an insect infection model. PMID:27001537

  20. Evaluation of aldosterone excretion in very low birth weight infants.

    PubMed

    Abdel Mohsen, Abdel Hakeem; Taha, Gamal; Kamel, Bothina A; Maksood, Mohamed Abdel

    2016-01-01

    Data about aldosterone production and excretion in the neonatal period are still few and controversial. Our objectives are to assess urinary aldosterone excretion (UAE) in very low birth weight (VLBW) infants and to identify clinical and biochemical variables that may influence this excretion. Thirty VLBW infants (14 males and 16 females), their gestational age <32 weeks and body weight <1500 g, were included in the study. Demographic and clinical data were recorded, within the first 72 h of life and urine and blood samples were collected for the measurement of urinary aldosterone and serum potassium, sodium, and chloride. The mean UAE value was 0.176 ± 0.05 μg/24 h and the mean absolute UAE was 1906 ± 271 pg/mL. There was a statistically significant positive correlation between UAE and gestational age and birth weight; also, infants with respiratory distress syndrome had higher urinary aldosterone levels than infants without respiratory distress. Only plasma sodium was a significant independent factor that negatively influenced UAE on linear regression analysis. The renin-angiotensin-aldosterone system of VLBW infants seems to be able, even immediately after birth, to respond to variations of plasma sodium concentrations; measurement of UAE constitutes an interesting method to determine aldosterone production in VLBW infants. PMID:27424689

  1. Biliary excretion of iron and ferritin in idiopathic hemochromatosis

    SciTech Connect

    Hultcrantz, R.; Angelin, B.; Bjoern-Rasmussen, E.E.; Ewerth, S.; Einarsson, K.

    1989-06-01

    The role of biliary excretion of iron and ferritin in iron overload was studied and evaluated. Ten patients with idiopathic hemochromatosis and two groups of controls (14 gallstone patients and 16 healthy subjects) were included. Liver tissue (obtained by percutaneous or operative biopsy) was investigated with light microscopy and transmission electron microscopy in combination with x-ray microanalysis. Fasting bile samples were obtained through duodenal aspiration or at cholecystectomy. Iron was determined in liver tissue and bile using atomic absorption spectroscopy, and ferritin was determined in serum and bile with a radioimmunoassay technique. All patients with hemochromatosis had iron-positive staining as seen in light microscopy. Electron microscopy showed iron-containing proteins in the lysosomes and cytosol of liver parenchymal cells, and this observation was supported by x-ray microanalysis. Hepatic iron concentration was increased about eightfold in the patients with hemochromatosis (p less than 0.001). Biliary iron concentration, expressed per millimole of bile acid, was increased about twofold (p less than 0.05) and biliary ferritin concentration about fivefold (p less than 0.001) in hemochromatosis. Four of the patients with hemochromatosis were reexamined after completed treatment with venesection; this resulted in normalized biliary concentrations of iron and ferritin. We conclude that biliary secretion of ferritin occurs in humans and that both iron and ferritin excretion are enhanced in hepatic iron overload. The apparently limited capacity of biliary iron excretion may be of importance for the hepatic iron accumulation in hemochromatosis.

  2. Inhibition of prostacyclin and thromboxane biosynthesis in healthy volunteers by single and multiple doses of acetaminophen and indomethacin.

    PubMed

    Schwartz, Jules I; Musser, Bret J; Tanaka, Wesley K; Taggart, William V; Mehta, Anish; Gottesdiener, Keith M; Greenberg, Howard E

    2015-09-01

    This double-blind, randomized crossover study assessed the effect of acetaminophen (1000 mg every 8 hours) versus indomethacin (50 mg every 8 hours) versus placebo on cyclooxygenase enzymes (COX-1 and COX-2). Urinary excretion of 2,3-dinor-6-keto-PGF1α, (prostacyclin metabolite, PGI-M; COX-2 inhibition) and 11-dehydro thromboxane B2 (thromboxane metabolite, Tx-M; COX-1 inhibition) were measured after 1 dose and 5 days of dosing. Peak inhibition of urinary metabolite excretion across 8 hours following dosing was the primary end point. Mean PGI-M excretion was 33.7%, 55.9%, and 64.6% on day 1 and 49.4%, 65.1%, and 80.3% on day 5 (placebo, acetaminophen, and indomethacin, respectively). Acetaminophen and indomethacin inhibited PGI-M excretion following single and multiple doses (P = .004 vs placebo). PGI-M excretion inhibition after 1 dose was similar for indomethacin and acetaminophen, but significantly greater with indomethacin after multiple doses (P = .006). Mean Tx-M excretion was 16.2%, 45.2%, and 86.6% on day 1 and 46.2%, 58.4%, and 92.6% on day 5 (placebo, acetaminophen, and indomethacin, respectively). Tx-M excretion inhibition following 1 dose was reduced by acetaminophen (P ≤ .003). Indomethacin reduced Tx-M excretion significantly more than acetaminophen and placebo after single and multiple doses (P ≤ .001). Acetaminophen and indomethacin inhibited COX-1 and COX-2 following a single dose, but acetaminophen was a less potent COX-1 inhibitor than indomethacin. PMID:27137142

  3. Metabolism of pyridalyl in rats: excretion, distribution, and biotransformation of dichloropropenyl-labeled pyridalyl.

    PubMed

    Nagahori, Hirohisa; Tomigahara, Yoshitaka; Isobe, Naohiko; Kaneko, Hideo

    2009-11-25

    Metabolism of pyridalyl [2,6-dichloro-4-(3,3-dichloroallyloxy)phenyl 3-[5-(trifluoromethyl)-2-pyridyloxy]propyl ether] labeled at position 2 of the dichloropropenyl group with 14C was investigated after single oral administration to male and female rats at 5 and 500 mg/kg. Absorbed 14C was excreted into feces (68-79%), urine (8-14%), and expired air (6-10%) in all of the groups. Regarding 14C-tissue residues on the seventh day after administration, fat showed the highest levels at 0.98-2.34 ppm and 219-221 ppm with the low and high doses, respectively. 14C-Residues in other tissues accounted for 0.03-0.32 ppm at the low dose and 3-70 ppm at the high dose. The percentages of the 14C-residue in fat were 1.50-3.16% of the dose, and those of muscle and hair and skin were also relatively high, accounting for 0.49-1.20%. Total 14C-residues in the whole body were 2.95-6.80% of the dose. Fecal metabolites in male rats treated with 500 mg/kg pyridalyl were purified by a combination of chromatographic techniques, and chemical structures of 8 metabolites were identified by NMR and MS spectrometry. The biotransformation reactions in rats were proposed to be as follows: (1) epoxidation of the double bond in the dichloropropenyl group followed by hydration, dehydrochlorination, decarboxylation, and/or mercapturic acid conjugation; (2) CO2 formation after O-dealkylation of pyridalyl and its metabolites; (3) hydroxylation of C3 in the pyridyl ring; (4) O-dealkylation of the pyridyloxy and the trimethylene groups; (5) dehydrochlorination and hydration in the dichloropropenyl group. PMID:19919122

  4. Endocytotic Uptake of Zoledronic Acid by Tubular Cells May Explain Its Renal Effects in Cancer Patients Receiving High Doses of the Compound

    PubMed Central

    Verhulst, Anja; Sun, Shuting; McKenna, Charles E.; D’Haese, Patrick C.

    2015-01-01

    Zoledronic acid, a highly potent nitrogen-containing bisphosphonate used for the treatment of pathological bone loss, is excreted unmetabolized via the kidney if not bound to the bone. In cancer patients receiving high doses of the compound renal excretion may be associated with acute tubular necrosis. The question of how zoledronic acid is internalized by renal tubular cells has not been answered until now. In the current work, using a primary human tubular cell culture system, the pathway of cellular uptake of zoledronic acid (fluorescently/radiolabeled) and its cytotoxicity were investigated. Previous studies in our laboratory have shown that this primary cell culture model consistently mimics the physiological characteristics of molecular uptake/transport of the epithelium in vivo. Zoledronic acid was found to be taken up by tubular cells via fluid-phase-endocytosis (from apical and basolateral side) as evidenced by its co-localization with dextran. Cellular uptake and the resulting intracellular level was twice as high from the apical side compared to the basolateral side. Furthermore, the intracellular zoledronic acid level was found to be dependent on the administered concentration and not saturable. Cytotoxic effects however, were only seen at higher administration doses and/or after longer incubation times. Although zoledronic acid is taken up by tubular cells, no net tubular transport could be measured. It is concluded that fluid-phase-endocytosis of zoledronic acid and cellular accumulation at high doses may be responsible for the acute tubular necrosis observed in some cancer patients receiving high doses of the compound. PMID:25756736

  5. Phase 1 Study of VEGF Trap (Aflibercept) Administered Subcutaneously to Patients with Advanced Solid Tumors

    PubMed Central

    Tew, William P.; Gordon, Michael; Murren, John; Dupont, Jakob; Pezzulli, Sandra; Aghajanian, Carol; Sabbatini, Paul; Mendelson, David; Schwartz, Lawrence; Gettinger, Scott; Psyrri, Amanda; Cedarbaum, Jesse M.; Spriggs, David R.

    2014-01-01

    Purpose To determine the maximum tolerated dose (MTD) or maximal administered dose (MAD) and pharmacokinetic and safety profiles of subcutaneously administered VEGF Trap (aflibercept), a novel anti-angiogenic agent. Experimental Design In this open-label, dose-escalation study, patients with advanced solid tumors were treated with subcutaneous doses of aflibercept at seven dose levels. Patients received a single dose of aflibercept and then underwent safety and pharmacokinetic assessments over the next 4 weeks. Patients then received weekly or bi-weekly treatment over the subsequent 6 weeks. Patients tolerating and benefiting could continue on aflibercept at the same dose and schedule until progression of disease. Results Thirty-eight patients received at least one dose of aflibercept. MTD was not reached. Due to solubility/dosing limits with the subcutaneous formulation, 1600mcg/kg/week was the MAD. The most common toxicities were proteinuria (37%), fatigue (32%), injection site reactions (18%), nausea (17%), myalgia and anorexia (16% each), hypertension (13%), and voice hoarseness (11%). Drug-related grade 3–4 toxicity was uncommon (7%) and reversible: dehydration, cerebral ischemia, proteinuria, hypertension, leukopenia, and pulmonary embolism. We identified dose-proportional increases in plasma concentrations of aflibercept bound to VEGF with a t1/2 of 18 days. No anti-aflibercept antibodies were detected. Stable disease was maintained for at least 10 weeks in 18 patients (47%), and 2 patients maintained on study for more than 1 year. Conclusion Subcutaneous aflibercept was well-tolerated and had manageable side effects. Its favorable pharmacokinetic profile and potential antitumor activity warrants further evaluation. PMID:20028764

  6. Dosimetry and toxicity of Samarium-153-EDTMP administered for bone pain due to skeletal metastases

    SciTech Connect

    Bayouth, J.E.; Macey, D.J.; Kasi, L.P.

    1994-01-01

    Palliation of bone pain in patients with cancer metastatic to bone is being evaluated in several cancer centers by the administration of the bone-seeking phosphonate ethylenediaminetetramethylenephosphonic acid (EDTMP) chelated with the beta particle-emitting radionuclide {sup 153}Sm. In this study {sup 153}Sm-EDTMP was intravenously injected into 19 patients over a 1-min period. Patients received up to four injections of 18.5 MBq (0.5 mCi) or 37 MBq (1.0mCi) per kilogram of body weight. Skeletal retention was calculated from urinary excretion. No uptake of {sup 153}Sm-EDTMP in nonskeletal tissues was observed in whole-body gamma camera images. The mean skeletal uptake for all patients was 54% {plus_minus} 16% of the injected dose (%ID). This resulted in the bone marrow receiving 89 cGy/GBq {plus_minus} 27 cGy/GBq (3.28 cGy/mCi {plus_minus} 0.99 cGy/mCi), with calculated marrow doses ranging from 27 cGy to 338 cGy. For each patient, the estimated radiation absorbed dose to the marrow was correlated to the percent decrease in platelet number, ranging from 7.4% to 78.9%. Since the deviation of uptake between the four injections for a given patient (7.6% ID) was less than the deviation for all patients (16% ID), the initial dose may be used to estimate the skeletal uptake for the remaining doses. These radiation dose estimates permit patients at risk to be identified prior to reaching myelotoxicity and develop dose-response models. Thirteen patients (68%) reported significant pain relief from this radionuclide therapy. Bone pain appears to be alleviated by {sup 153}Sm-EDTMP with limited red marrow doses and no toxic effects in other organs. 15 refs., 8 figs., 2 figs.

  7. Efficacy of a novel chitosan formulation on fecal fat excretion: a double-blind, crossover, placebo-controlled study.

    PubMed

    Barroso Aranda, Jorge; Contreras, Francisco; Bagchi, Debasis; Preuss, Harry G

    2002-01-01

    The ability of a novel chitosan formulation to influence gastrointestinal fat absorption in vivo was examined in a double-blind, placebo-controlled, crossover study by determining the content of total fat in feces in two groups of subjects. Twenty-nine normal healthy subjects were recruited for the study. Twenty-four participants completed the test period with the chitosan formulation, and 21 completed the placebo phase of study. During the placebo and the test periods, the subjects were administered six capsules three times daily 10 minutes before meals for three days and for the two days of the stool collection. A daily serving of six tablets of the test compound contained 2100 mg chitosan and 300 mg psyllium husk seeds. In respect to the baseline period, the test compound increased fat excretion significantly whether the test period preceded or proceeded the placebo period (p<0.02 and p<0.05 respectively). In contrast, essentially no changes were seen during the placebo loading periods. Compared to the difference between placebo period and its baseline period, a statistically significant increase in fecal fat excretion was observed over baseline following oral supplementation of a novel formulation of chitosan and psyllium husk seeds [+3.63 gm/day +/- 0.83 (SEM) vs. -0.15 gm/day +/- 0.94 (SEM) (p=0.004)]. The average daily increase in fecal fat of 3-4 grams over control could account for a decrease in calorie consumption of 30-40 kcal per day. A total of 19 subjects completed both parts of the study. Examining the data from these 19 subjects by ANOVA, it was found that the period when the test compounds were given was statistically significantly different from the placebo baseline, placebo experimental, and test baseline periods. Using multiple comparisons, it was ascertained that the novel formulation containing chitosan plus psyllium husk seeds increases fecal fat excretion. PMID:12939120

  8. Effectiveness of resistant starch, compared to guar gum, in depressing plasma cholesterol and enhancing fecal steroid excretion.

    PubMed

    Levrat, M A; Moundras, C; Younes, H; Morand, C; Demigné, C; Rémésy, C

    1996-10-01

    Amylase-resistant starch (RS) represents a substrate that can be administered in substantial amounts in the diet, in contrast to gel-forming polysaccharides, such as guar gum (GG). The aim of this work was thus to compare the effects of GG and RS on cholesterol metabolism in rats adapted to 0.4% cholesterol diets, using dietary GG or RS levels (8 or 20%, respectively) that led to a similar development of fermentations, as assessed by the degree of enlargement of the cecum. The RS diet elicited a marked rise in the cecal pool of short-chain fatty acids, especially acetic and butyric acid, whereas the GG diet favored high-propionic acid fermentations. Both polysaccharides markedly altered the cholesterol excretion, from 50% of ingested cholesterol in controls, up to about 70% in rats adapted to the RS or GG diets. With these diets, the fecal excretion of bile acids was enhanced (67 and 144% with the RS and GG diets, respectively). RS and GG diets were effective in lowering plasma cholesterol (about -40%) and triglycerides (-36%). There was practically no effect of the diets on cholesterol in d > 1.040 lipoproteins (high density lipoproteins), whereas RS (and to a larger extent, GG) were very effective to depress cholesterol in d < 1.040 lipoproteins (especially in triglyceride-rich lipoproteins). Fermentable polysaccharides counteracted the accumulation of cholesterol in the liver, especially cholesterol esters. In parallel, liver acyl CoA:cholesterol acyltransferase was depressed in rats fed the RS or GG diets, whereas only the GG diet counteracted the downregulation of 3-hydroxy-3-methylglutaryl-CoA by cholesterol. These data suggest that RS may be practically as effective as a gel-forming gum, such as GG, on steroid excretion and on cholesterol metabolism. PMID:8898306

  9. Toxicokinetics of acrylamide in rats and humans following single oral administration of low doses

    SciTech Connect

    Kopp, Eva Katharina; Dekant, Wolfgang

    2009-03-01

    The rodent carcinogen acrylamide (AA) is formed during preparation of starch-containing foods. AA is partly metabolized to the genotoxic epoxide glycidamide (GA). After metabolic processing, the mercapturic acids N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA), rac-N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine (GAMA) and rac-N-acetyl-S-(1-carbamoyl-moyl-2-hydroxyethyl)-L-cysteine (iso-GAMA) are excreted with urine. In humans, AAMA can be sulfoxidized to AAMA-sulfoxide. The aim of this study was to assess potential species-differences in AA-toxicokinetics in rats and humans after single oral administration of doses similar to the daily human dietary exposure. Male Fischer 344 rats (n = 5/dose group) were administered 20 and 100 {mu}g/kg b.w. {sup 13}C{sub 3}-AA in deionized water via oral gavage. Human subjects (n = 3/gender) were orally administered 0.5 and 20 {mu}g/kg b.w. {sup 13}C{sub 3}-AA with drinking water. Urine samples were collected in intervals for 96 and 94 h, respectively. Urinary concentrations of {sup 13}C{sub 3}-AAMA, {sup 13}C{sub 3}-GAMA and {sup 13}C{sub 3}-AAMA-sulfoxide were monitored by liquid chromatography-tandem mass spectrometry. The recovered urinary metabolites accounted for 66.3% and 70.5% of the 20 and 100 {mu}g/kg b.w. doses in rats and for 71.3% and 70.0% of the 0.5 and 20 {mu}g/kg b.w. doses in humans. In rats, {sup 13}C{sub 3}-AAMA accounted for 33.6% and 38.8% of dose and 32.7% and 31.7% of dose was recovered as {sup 13}C{sub 3}-GAMA; {sup 13}C{sub 3}-AAMA-sulfoxide was not detected in rat urine. In humans, {sup 13}C{sub 3}-AAMA, {sup 13}C{sub 3}-GAMA and {sup 13}C{sub 3}-AAMA-sulfoxide accounted for 51.7% and 49.2%, 6.3% and 6.4% and 13.2% and 14.5% of the applied dose, respectively. The obtained results suggest that the extent of AA bioactivation to GA in humans is lower than in rodents.

  10. Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and HPV-6/11/16/18 vaccine administered according to 2- and 3-dose schedules in girls aged 9-14 years: Results to month 12 from a randomized trial.

    PubMed

    Leung, Ting Fan; Liu, Anthony Pak-Yin; Lim, Fong Seng; Thollot, Franck; Oh, Helen May Lin; Lee, Bee Wah; Rombo, Lars; Tan, Ngiap Chuan; Rouzier, Roman; Friel, Damien; De Muynck, Benoit; De Simoni, Stéphanie; Suryakiran, Pemmaraju; Hezareh, Marjan; Folschweiller, Nicolas; Thomas, Florence; Struyf, Frank

    2015-01-01

    This observer-blind study (clinicaltrials.gov NCT01462357) compared the immunogenicity and safety of 2 doses of the HPV-16/18 AS04-adjuvanted vaccine (HPV-16/18(2D)) vs. 2 or 3 doses of the HPV-6/11/16/18 vaccine (HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D)) in healthy girls aged 9-14 y. Girls were randomized (1:1:1) to receive HPV-16/18(2D) at months (M) 0,6 (N = 359), HPV-6/11/16/18(2D) at M0,6 (N = 358) or HPV-6/11/16/18(3D) at M0,2,6 (N = 358). The primary objective was non-inferiority/superiority of HPV-16/18 antibodies by ELISA for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) at M7 in the according-to-protocol immunogenicity cohort (ATP-I) and total vaccinated cohort, respectively. Secondary objectives included non-inferiority/superiority of HPV-16/18(2D) vs. HPV-6/11/16/18(3D) at M7, non-inferiority/superiority at M12, HPV-16/18 neutralizing antibodies, frequencies of T-cells/B-cells, reactogenicity and safety. Antibody responses at M7 for HPV-16/18(2D) were superior to those for HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D) (lower limit of 95% confidence interval for geometric mean titer ratio (GMR) was >1): HPV-16/18(2D)/HPV-6/11/16/18(2D) GMRs were 1.69 [1.49-1.91] for anti-HPV-16 and 4.52 [3.97-5.13] for anti-HPV-18; HPV-16/18(2D)/HPV-6/11/16/18(3D) GMRs were 1.72 [1.54-1.93] for anti-HPV-16 and 3.22 [2.82-3.68] for anti-HPV-18; p = 0.0001 for all comparisons. Non-inferiority/superiority was also demonstrated at M12. Among initially seronegative girls in the ATP-I, neutralizing antibody titers were at least 1.8-fold higher for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D) at M7 and M12. Frequencies of HPV-16/18-specific T-cells and B-cells were in similar ranges between groups. Reactogenicity and safety were in line with the known profile of each vaccine. In conclusion, superior HPV-16/18 antibody responses were elicited by 2 doses of the HPV-16/18 AS04-adjuvanted vaccine compared with 2 or 3 doses of the HPV-6/11/16/18 vaccine in girls (9-14 years

  11. Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and HPV-6/11/16/18 vaccine administered according to 2- and 3-dose schedules in girls aged 9–14 years: Results to month 12 from a randomized trial

    PubMed Central

    Leung, Ting Fan; Liu, Anthony Pak-Yin; Lim, Fong Seng; Thollot, Franck; Oh, Helen May Lin; Lee, Bee Wah; Rombo, Lars; Tan, Ngiap Chuan; Rouzier, Roman; Friel, Damien; De Muynck, Benoit; De Simoni, Stéphanie; Suryakiran, Pemmaraju; Hezareh, Marjan; Folschweiller, Nicolas; Thomas, Florence; Struyf, Frank

    2015-01-01

    This observer-blind study (clinicaltrials.gov NCT01462357) compared the immunogenicity and safety of 2 doses of the HPV-16/18 AS04-adjuvanted vaccine (HPV-16/18(2D)) vs. 2 or 3 doses of the HPV-6/11/16/18 vaccine (HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D)) in healthy girls aged 9–14 y. Girls were randomized (1:1:1) to receive HPV-16/18(2D) at months (M) 0,6 (N = 359), HPV-6/11/16/18(2D) at M0,6 (N = 358) or HPV-6/11/16/18(3D) at M0,2,6 (N = 358). The primary objective was non-inferiority/superiority of HPV-16/18 antibodies by ELISA for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) at M7 in the according-to-protocol immunogenicity cohort (ATP-I) and total vaccinated cohort, respectively. Secondary objectives included non-inferiority/superiority of HPV-16/18(2D) vs. HPV-6/11/16/18(3D) at M7, non-inferiority/superiority at M12, HPV-16/18 neutralizing antibodies, frequencies of T-cells/B-cells, reactogenicity and safety. Antibody responses at M7 for HPV-16/18(2D) were superior to those for HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D) (lower limit of 95% confidence interval for geometric mean titer ratio (GMR) was >1): HPV-16/18(2D)/HPV-6/11/16/18(2D) GMRs were 1.69 [1.49–1.91] for anti-HPV-16 and 4.52 [3.97–5.13] for anti-HPV-18; HPV-16/18(2D)/HPV-6/11/16/18(3D) GMRs were 1.72 [1.54–1.93] for anti-HPV-16 and 3.22 [2.82–3.68] for anti-HPV-18; p = 0.0001 for all comparisons. Non-inferiority/superiority was also demonstrated at M12. Among initially seronegative girls in the ATP-I, neutralizing antibody titers were at least 1.8-fold higher for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D) at M7 and M12. Frequencies of HPV-16/18-specific T-cells and B-cells were in similar ranges between groups. Reactogenicity and safety were in line with the known profile of each vaccine. In conclusion, superior HPV-16/18 antibody responses were elicited by 2 doses of the HPV-16/18 AS04-adjuvanted vaccine compared with 2 or 3 doses of the HPV-6/11/16/18 vaccine in girls (9–14

  12. Practical applications of internal dose calculations

    SciTech Connect

    Carbaugh, E.H.

    1994-06-01

    Accurate estimates of intake magnitude and internal dose are the goal for any assessment of an actual intake of radioactivity. When only one datum is available on which to base estimates, the choices for internal dose assessment become straight-forward: apply the appropriate retention or excretion function, calculate the intake, and calculate the dose. The difficulty comes when multiple data and different types of data become available. Then practical decisions must be made on how to interpret conflicting data, or how to adjust the assumptions and techniques underlying internal dose assessments to give results consistent with the data. This article describes nine types of adjustments which can be incorporated into calculations of intake and internal dose, and then offers several practical insights to dealing with some real-world internal dose puzzles.

  13. The combination of ezetimibe and ursodiol promotes fecal sterol excretion and reveals a G5G8-independent pathway for cholesterol elimination[S

    PubMed Central

    Wang, Yuhuan; Liu, Xiaoxi; Pijut, Sonja S.; Li, Jianing; Horn, Jamie; Bradford, Emily M.; Leggas, Markos; Barrett, Terrence A.; Graf, Gregory A.

    2015-01-01

    Previous studies suggest an interdependent relationship between liver and intestine for cholesterol elimination from the body. We hypothesized that a combination of ursodiol (Urso) and ezetimibe (EZ) could increase biliary secretion and reduce cholesterol reabsorption, respectively, to promote cholesterol excretion. Treatment with Urso increased hepatic ABCG5 ABCG8 (G5G8) protein and both biliary and fecal sterols in a dose-dependent manner. To determine whether the drug combination (Urso-EZ) further increased cholesterol excretion, mice were treated with Urso alone or in combination with two doses of EZ. EZ produced an additive and dose-dependent increase in fecal neutral sterol (FNS) elimination in the presence of Urso. Finally, we sequentially treated wide-type and G5G8-deficient mice with Urso and Urso-EZ to determine the extent to which these effects were G5G8 dependent. Although biliary and FNS were invariably lower in G5G8 KO mice, the relative increase in FNS following treatment with Urso alone or the Urso-EZ combination was not affected by genotype. In conclusion, Urso increases G5G8, biliary cholesterol secretion, and FNS and acts additively with EZ to promote fecal sterol excretion. However, the stimulatory effect of these agents was not G5G8 dependent. PMID:25635125

  14. The combination of ezetimibe and ursodiol promotes fecal sterol excretion and reveals a G5G8-independent pathway for cholesterol elimination.

    PubMed

    Wang, Yuhuan; Liu, Xiaoxi; Pijut, Sonja S; Li, Jianing; Horn, Jamie; Bradford, Emily M; Leggas, Markos; Barrett, Terrence A; Graf, Gregory A

    2015-04-01

    Previous studies suggest an interdependent relationship between liver and intestine for cholesterol elimination from the body. We hypothesized that a combination of ursodiol (Urso) and ezetimibe (EZ) could increase biliary secretion and reduce cholesterol reabsorption, respectively, to promote cholesterol excretion. Treatment with Urso increased hepatic ABCG5 ABCG8 (G5G8) protein and both biliary and fecal sterols in a dose-dependent manner. To determine whether the drug combination (Urso-EZ) further increased cholesterol excretion, mice were treated with Urso alone or in combination with two doses of EZ. EZ produced an additive and dose-dependent increase in fecal neutral sterol (FNS) elimination in the presence of Urso. Finally, we sequentially treated wide-type and G5G8-deficient mice with Urso and Urso-EZ to determine the extent to which these effects were G5G8 dependent. Although biliary and FNS were invariably lower in G5G8 KO mice, the relative increase in FNS following treatment with Urso alone or the Urso-EZ combination was not affected by genotype. In conclusion, Urso increases G5G8, biliary cholesterol secretion, and FNS and acts additively with EZ to promote fecal sterol excretion. However, the stimulatory effect of these agents was not G5G8 dependent. PMID:25635125

  15. Liquid paraffins in feed enhance fecal excretion of mirex and DDE from body stores of lactating goats and cows

    SciTech Connect

    Rozman, K.; Rozman, T.; Smith, G.S.

    1984-01-01

    Contamination of livestock with halogenated hydrocarbons has caused large economic losses in the past; not so much because of acute toxicity to animals but mainly because their high lipid solubility is frequently accompanied by low biodegradation resulting in prolonged half-lives. Liquid paraffins administered in the feed were shown to promote removal of lipophilic pesticides to the diet enhanced fecal elimination of hexachlorobenzene from body stores in rats and rhesus monkeys by ehnancing excretion with feces. Addition of white mineral oil or n-hexadecane from body stores of growing lambs without adverse effects on feed intake or diet digestibility. This study examined effects of liquid paraffins added to the feed on the disposition of /sup 14/C-mirex in lactating goats under laboratory conditions and effects of white mineral oil in the feed on levels of DDE in body fat, milk and feces of dairy cattle in a field trail.

  16. 40 CFR 147.1700 - State-administered program.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 24 2012-07-01 2012-07-01 false State-administered program. 147.1700 Section 147.1700 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS North Carolina § 147.1700 State-administered program. The...

  17. 40 CFR 147.2500 - State-administered program.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 24 2012-07-01 2012-07-01 false State-administered program. 147.2500 Section 147.2500 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Wisconsin § 147.2500 State-administered program. The...

  18. 40 CFR 147.1450 - State-administered program.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 23 2011-07-01 2011-07-01 false State-administered program. 147.1450 Section 147.1450 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Nevada § 147.1450 State-administered program. The UIC...

  19. 40 CFR 147.2351 - EPA-administered program.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virginia § 147.2351 EPA-administered program. (a) Contents. The UIC program for the State of Virginia, including all Indian lands, is administered by EPA. This program consists of the UIC program requirements of 40...

  20. 40 CFR 147.2351 - EPA-administered program.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virginia § 147.2351 EPA-administered program. (a) Contents. The UIC program for the State of Virginia, including all Indian lands, is administered by EPA. This program consists of the UIC program requirements of 40...

  1. 40 CFR 147.2351 - EPA-administered program.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virginia § 147.2351 EPA-administered program. (a) Contents. The UIC program for the State of Virginia, including all Indian lands, is administered by EPA. This program consists of the UIC program requirements of 40...

  2. 40 CFR 147.2351 - EPA-administered program.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virginia § 147.2351 EPA-administered program. (a) Contents. The UIC program for the State of Virginia, including all Indian lands, is administered by EPA. This program consists of the UIC program requirements of 40...

  3. 40 CFR 147.1651 - EPA-administered program.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS New York § 147.1651 EPA-administered program. (a) Contents. The UIC program for the State of New York, including all Indian lands, is administered by EPA. The program consists of the UIC program requirements of 40...

  4. 40 CFR 147.1651 - EPA-administered program.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS New York § 147.1651 EPA-administered program. (a) Contents. The UIC program for the State of New York, including all Indian lands, is administered by EPA. The program consists of the UIC program requirements of 40...

  5. 40 CFR 147.1201 - EPA-administered program.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Minnesota § 147.1201 EPA-administered program. (a) Contents. The UIC program for the State of Minnesota is administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148, and...

  6. 40 CFR 147.1201 - EPA-administered program.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Minnesota § 147.1201 EPA-administered program. (a) Contents. The UIC program for the State of Minnesota is administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148, and...

  7. 40 CFR 147.1201 - EPA-administered program.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Minnesota § 147.1201 EPA-administered program. (a) Contents. The UIC program for the State of Minnesota is administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148, and...

  8. 40 CFR 147.1201 - EPA-administered program.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Minnesota § 147.1201 EPA-administered program. (a) Contents. The UIC program for the State of Minnesota is administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148, and...

  9. 40 CFR 147.2751 - EPA-administered program.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... lands, is administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.2751... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS American Samoa §...

  10. 40 CFR 147.2701 - EPA-administered program.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Indian lands, is administered by EPA. This program consists of the UIC program requirements of 40 CFR... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.2701... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virgin Islands §...

  11. 40 CFR 147.601 - EPA-administered program.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.601... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Hawaii § 147.601...

  12. 40 CFR 147.1151 - EPA-administered program.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Indian lands, is administered by EPA. This program consists of the UIC program requirements of 40 CFR... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.1151... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Michigan §...

  13. 40 CFR 147.801 - EPA-administered program.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.801... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Iowa § 147.801...

  14. 40 CFR 147.901 - EPA-administered program.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... lands, is administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.901... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Kentucky § 147.901...

  15. 40 CFR 147.2151 - EPA-administered program.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Tennessee § 147.2151 EPA-administered program. (a) Contents. The UIC program for the State of Tennessee, including all Indian lands, is administered by EPA. This program consists of the UIC program requirements of 40...

  16. 40 CFR 147.2151 - EPA-administered program.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Tennessee § 147.2151 EPA-administered program. (a) Contents. The UIC program for the State of Tennessee, including all Indian lands, is administered by EPA. This program consists of the UIC program requirements of 40...

  17. 40 CFR 147.2151 - EPA-administered program.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Tennessee § 147.2151 EPA-administered program. (a) Contents. The UIC program for the State of Tennessee, including all Indian lands, is administered by EPA. This program consists of the UIC program requirements of 40...

  18. Renal excretion of water in men under hypokinesia and physical exercise with fluid and salt supplementation

    NASA Astrophysics Data System (ADS)

    Zorbas, Yan G.; Federenko, Youri F.; Togawa, Mitsui N.

    It has been suggested that under hypokinesia (reduced number of steps/day) and intensive physical exercise, the intensification of fluid excretion in men is apparently caused as a result of the inability of the body to retain optimum amounts of water. Thus, to evaluate this hypothesis, studies were performed with the use of fluid and sodium chloride (NaCl) supplements on 12 highly trained physically healthy male volunteers aged 19-24 years under 364 days of hypokinesis (HK) and a set of intensive physical exercises (PE). They were divided into two groups with 6 volunteers per group. The first group of subjects were submitted to HK and took daily fluid and salt supplements in very small doses and the second group of volunteers were subjected to intensive PE and fluid-salt supplements. For the simulation of the hypokinetic effect, both groups of subjects were kept under an average of 4000 steps/day. During the prehypokinetic period of 60 days and under the hypokinetic period of 364 days water consumed and eliminated in urine by the men, water content in blood, plasma volume, rate of glomerular filtration, renal blood flow, osmotic concentration of urine and blood were measured. Under HK, the rate of renal excretion of water increased considerably in both groups. The additional fluid and salt intake failed to normalize water balance adequately under HK and PE. It was concluded that negative water balance evidently resulted not from shortage of water in the diet but from the inability of the body to retain optimum amounts of fluid under HK and a set of intensive PEs.

  19. Cisplatin based chemotherapy in testicular cancer patients: long term platinum excretion and clinical effects.

    PubMed

    Hohnloser, J H; Schierl, R; Hasford, B; Emmerich, B

    1996-09-20

    Patients with advanced testicular cancer (TC) have a very good long-term prognosis owing to cisplatin-based polychemotherapy. Platinum is believed to be excreted at a rapid rate via urine within weeks after chemotherapy. As a new, highly sensitive method has become available detecting even natural background platinum levels in body fluids, this study was set up to analyze urinary and serum platinum levels in long-term survivors of testicular neoplasm after cisplatin based polychemotherapy and to correlate clinical data with urinary and serum platinum levels. Urinary platinum concentrations were measured in 64 healthy controls (C) and 22 male patients (TC) 150 to 3022 days after the last application of i.v. cisplatin using voltammetry after UV-photolysis. In the latter group (TC), serum platinum levels were measured as well. Clinical data were analysed as to long-term organ toxicity. Mean urinary platinum levels were 2700 times higher in the patient group (TC) than natural background noise (p < 0.0001). There was a decline of urinary and serum platinum levels over time, being significantly above normal even 8 years after cisplatin exposure. The only significant variables related to the urine platinum concentration were a) the interval between the last i.v. cisplatin application and time of study and b) the total dose given. Not significant were the number of chemotherapy cycles, pre-therapy renal disease, patient age, tumour resection before/after chemotherapy, site of pre/post therapy resection, clinical staging, histological subtypes or tumour markers. Post-therapy renal disease or peripheral nerve damage were not significantly associated with urinary platinum levels. Our data indicate that even 8 years after cisplatin based chemotherapy 500 times elevated urinary and serum platinum levels can be measured in testicular cancer patients. No organ toxicity related to long-term platinum excretion could be detected. This may be due to our small sample size. PMID

  20. Aspartame ingestion increases urinary calcium, but not oxalate excretion, in healthy subjects.

    PubMed

    Nguyen, U N; Dumoulin, G; Henriet, M T; Regnard, J

    1998-01-01

    Aspartame is the artificial sweetener most extensively used as a substitute for glucose or sucrose in the food industry, particularly in soft drinks. As glucose ingestion increases calciuria and oxaluria, the two main determinants of urinary calcium-oxalate saturation, we considered it worthwhile to determine whether aspartame ingestion also affects calcium-oxalate metabolism. Our study compares the effects of the ingestion of similarly sweet doses of aspartame (250 mg) and glucose (75 g) on calcium and oxalate metabolisms of seven healthy subjects. Urinary calcium excretion increased after the intake of both aspartame (+86%; P < 0.01) and glucose (+124%; P < 0.01). This may be due to the rise in calcemia observed after both aspartame (+2.2%; P < 0.05) and glucose ingestion (+1.8%; P < 0.05). The increased calcemia may be linked to the decrease in phosphatemia that occurred after both aspartame (P < 0.01) and glucose (P < 0.01) load. Aspartame did not alter glycemia or insulinemia, whereas glucose intake caused striking increases in both glycemia (+59%; P < 0.001) and insulinemia (+869%; P < 0.01). Although insulin was considered the main calciuria-induced factor after glucose load, it is unlikely that this mechanism played a role with aspartame. Urinary oxalate excretion did not change after aspartame, whereas it increased (+27%; P < 0.05) after glucose load. Thus, as aspartame induced a similar increase in calciuria as did glucose but, conversely, no change in oxaluria, substituting glucose by aspartame in soft drinks may appear to be of some potential benefit. PMID:9435435

  1. The Effects of Angiotensin II on Renal Water and Electrolyte Excretion in Normal and Caval Dogs*

    PubMed Central

    Porush, Jerome G.; Kaloyanides, George J.; Cacciaguida, Roy J.; Rosen, Stanley M.

    1967-01-01

    The effects of intravenous administration of angiotensin II on renal water and electrolyte excretion were examined during hydropenia, water diuresis, and hypotonic saline diuresis in anesthetized normal dogs and dogs with thoracic inferior vena cava constriction and ascites (caval dogs). The effects of unilateral renal artery infusion of a subpressor dose were also examined. During hydropenia angiotensin produced a decrease in tubular sodium reabsorption, with a considerably greater natriuresis in caval dogs, and associated with a decrease in free water reabsorption (TcH2O). Water and hypotonic saline diuresis resulted in an augmented angiotensin natriuresis, with a greater effect still observed in caval dogs. In these experiments free water excretion (CH2O) was limited to 8-10% of the glomerular filtration rate (GFR), although distal sodium load increased in every instance. In the renal artery infusion experiments a significant ipsilateral decrease in tubular sodium reabsorption was induced, particularly in caval dogs. These findings indicate that angiotensin has a direct effect on renal sodium reabsorption unrelated to a systemic circulatory alteration. The attenuation or prevention of the falls in GFR and effective renal plasma flow (ERPF) usually induced by angiotensin may partially account for the greater natriuretic response in caval dogs and the augmentation during water or hypotonic saline diuresis. However, a correlation between renal hemodynamics and the degree of natriuresis induced was not always present and, furthermore, GFR and ERPF decreased significantly during the intrarenal artery infusion experiments. Therefore, the present experiments indicate that another mechanism is operative in the control of the angiotensin natriuresis and suggest that alterations in intrarenal hemodynamics may play a role. The decrease in TcH2O and the apparent limitation of CH2O associated with an increase in distal sodium load localize the site of action of angiotensin

  2. Urinary excretion and daily intake rates of diethyl phthalate in the general Canadian population.

    PubMed

    Saravanabhavan, Gurusankar; Walker, Mike; Guay, Mireille; Aylward, Lesa

    2014-12-01

    We have analyzed the trends in the body-weight-adjusted urinary monoethyl phthalate (MEP) concentrations and the diethyl ethyl phthalate (DEP) daily intake estimates in the general Canadian population (aged 6-49 years) using the Canadian Health Measures Survey 2007-2009 dataset. The creatinine correction approach, as well as the urine volume approach in a simple one compartment model were used to calculate the daily urinary MEP excretion rates and DEP intake rates in individual survey participants. Using multiple regression models, we have estimated least square geometric means (LSGMs) of body-weight-adjusted MEP concentration, daily excretion and intake rates among different age groups and sex. We observed that body weight affects the trends in the MEP concentrations significantly among children (aged 6-11 years), adolescents (aged 12-19 years) and adults (aged 20-49 years). The body-weight-adjusted MEP concentrations in children were significantly higher than those in adults. On the other hand the DEP daily intakes in children were significantly lower than those in adults. We did not observe any differences in the DEP daily intake rates between males and females. Although the urinary MEP concentrations are correlated well with DEP daily intake estimates in the overall population, one should be cautious when directly using the urinary concentrations to compare the intake trends in the sub-populations (e.g. children vs. adults) as these trends are governed by additional physiological factors. The DEP daily intake calculated using the creatinine approach and that using the urine volume approach were similar to each other. The estimated geometric mean and 95th percentile of DEP daily intake in the general Canadian population are 2 and 20 μg/kg-bw/day, respectively. These daily intake estimates are significantly lower than the US Environmental Protection Agency's oral reference dose of 800 μg/kg-bw/day. PMID:25217994

  3. Excretion of endogenous boldione in human urine: influence of phytosterol consumption.

    PubMed

    Verheyden, Karolien; Noppe, Herlinde; Vanhaecke, Lynn; Wille, Klaas; Bussche, Julie Vanden; Bekaert, Karen; Thas, Olivier; Janssen, Colin R; De Brabander, Hubert F

    2009-10-01

    Boldenone (17-hydroxy-androsta-1,4-diene-3-one, Bol) and boldione (androst-1,4-diene-3,17-dione, ADD), are currently listed as exogenous anabolic steroids by the World Anti-Doping Agency. However, it has been reported that these analytes can be produced endogenously. Interestingly, only for Bol a comment is included in the list on its potential endogenous origin. In this study, the endogenous origin of ADD in human urine was investigated, and the potential influence of phytosterol consumption was evaluated. We carried out a 5-week in vivo trial with both men (n=6) and women (n=6) and measured alpha-boldenone, beta-boldenone, boldione, androstenedione, beta-testosterone and alpha-testosterone in their urine using gas chromatography coupled to multiple mass spectrometry (GC-MS-MS). The results demonstrate that endogenous ADD is sporadically produced at concentrations ranging from 0.751 ng mL(-1) to 1.73 ng mL(-1), whereas endogenous Bol could not be proven. We also tested the effect of the daily consumption of a commercially available phytosterol-enriched yogurt drink on the presence of these analytes in human urine. Results from this study could not indicate a relation of ADD-excretion with the consumption of phytosterols at the recommended dose. The correlations between ADD and other steroids were consistently stronger for volunteers consuming phytosterols (test) than for those refraining from phytosterol consumption (control). Excretion of AED, bT and aT did not appear to be dependent on the consumption of phytosterols. This preliminary in vivo trial indicates the endogenous origin of boldione or ADD in human urine, independent on the presence of any structural related analytes such as phytosterols. PMID:19520162

  4. Comparison of Four Commercial One-Dose Porcine Circovirus Type 2 (PCV2) Vaccines Administered to Pigs Challenged with PCV2 and Porcine Reproductive and Respiratory Syndrome Virus at 17 Weeks Postvaccination To Control Porcine Respiratory Disease Complex under Korean Field Conditions

    PubMed Central

    Park, Changhoon; Seo, Hwi Won; Han, Kiwon

    2014-01-01

    Under Korean field conditions, coinfection with porcine circovirus type 2 (PCV2) and porcine reproductive and respiratory syndrome virus (PRRSV) is most commonly observed in porcine respiratory disease complex (PRDC). Despite the wide use of PCV2 vaccination, PRDC remains a serious respiratory problem. Thus, the objective of this study was to determine and compare the efficacy of 4 one-dose PCV2 vaccines on 3-week-old pigs with an experimental PCV2-PRRSV challenge at 17 weeks postvaccination. Regardless of which commercial PCV2 vaccine was used, the vaccination of piglets at 3 weeks of age was efficacious against cochallenge of PCV2 and PRRSV, on the basis of growth performance and PCV2-associated lesions. However, the inactivated chimeric PCV1-2 and the PCV2 vaccines induced higher PCV2-specific neutralizing antibody (NA) titers and PCV2-specific gamma interferon-secreting cells and lower PCV2 viremia levels than the two PCV2 subunit vaccines. The vaccination of piglets against PCV2 at 3 weeks of age was effective in reducing PCV2 viremia and PCV2-associated lesions during the finishing period, which is an age at which pigs are frequently affected by PRDC caused by coinfection with PCV2 and PRRSV under Korean field conditions. PMID:24403524

  5. Diurnal nitrogen excretion rhythm of the functionally ureogenic gobiid fish Mugilogobius abei.

    PubMed

    Kajimura, Makiko; Iwata, Katsuya; Numata, Hideharu

    2002-02-01

    This study was performed to determine the daily periodicity of urea excretion in the ureogenic gobiid fish Mugilogobius abei. In 20% seawater, urea excretion of all the fish examined showed daily periodic changes under a 12-h light-dark cycle, and some showed a free-running rhythm under constant darkness. This is the first report of a circadian rhythm in urea excretion in fishes. Daily variations in urea excretion under light-dark cycles were also observed under various conditions, i.e. exposure to water ammonia, confinement/non-confinement and solitary/group. Due to the daily variations in urea excretion, urea contents in tissues changed periodically, whereas enzyme activities related to urea synthesis did not change significantly. The index of urea permeability as determined by changes in body urea contents after 2-h immersion of 25 mM urea solution was high during the peak of daily variation in urea excretion. Locomotor activity and urea excretion showed clear daily variations under light-dark cycles, both of which were diurnal. Furthermore, daily variations in urea excretion were maintained even when the diurnal pattern in the locomotor activity was disturbed. These results suggest that periodic urea excretion was mediated by periodic enhancement of permeability for urea at excretion sites. PMID:11818244

  6. Plasma cholesterol-lowering activity of gingerol- and shogaol-enriched extract is mediated by increasing sterol excretion.

    PubMed

    Lei, Lin; Liu, Yuwei; Wang, Xiaobo; Jiao, Rui; Ma, Ka Ying; Li, Yuk Man; Wang, Lijun; Man, Sun Wa; Sang, Shengmin; Huang, Yu; Chen, Zhen-Yu

    2014-10-29

    The present study investigated the cholesterol-lowering activity of gingerol- and shogaol-enriched ginger extract (GSE). Thirty hamsters were divided into three groups and fed the control diet or one of the two experimental diets containing 0.5 and 1.0% GSE. Plasma total cholesterol, liver cholesterol, and aorta atherosclerotic plaque were dose-dependently decreased with increasing amounts of GSE added into diets. The fecal sterol analysis showed dietary GSE increased the excretion of both neutral and acidic sterols in a dose-dependent manner. GSE down-regulated the mRNA levels of intestinal Niemann-Pick C1-like 1 protein (NPC1L1), acyl CoA:cholesterol acyltransferase 2 (ACAT2), microsomal triacylglycerol transport protein (MTP), and ATP binding cassette transporter 5 (ABCG5), whereas it up-regulated hepatic cholesterol-7α-hydroxylase (CYP7A1). It was concluded that beneficial modification of the lipoprotein profile by dietary GSE was mediated by enhancing excretion of fecal cholesterol and bile acids via up-regulation of hepatic CYP7A1 and down-regulation of mRNA of intestinal NPC1L1, ACAT2, and MTP. PMID:25290252

  7. A study on the effect of the internal exposure to (210)Po on the excretion of urinary proteins in rats.

    PubMed

    Sadi, Baki; Li, Chunsheng; Ko, Raymond; Daka, Joseph; Yusuf, Hamdi; Wyatt, Heather; Surette, Joel; Priest, Nick; Hamada, Nobuyuki

    2016-05-01

    This study was designed to assess the feasibility of a noninvasive urine specimen for the detection of proteins as indicators of internal exposure to ionizing radiation. Three groups of rats (five in each group) were intravenously injected with 1601 ± 376, 10,846 ± 591 and 48,467 ± 2812 Bq of (210)Po in citrate form. A sham-exposed control group of five rats was intravenously injected with sterile physiological saline. Daily urine samples were collected over 4 days following injection. Purification and pre-concentration of urinary proteins were carried out by ultrafiltration using a 3000 Da molecular weight cutoff membrane filter. The concentration of common urinary proteins, namely albumin, alpha-1-acid glycoprotein, immunoglobulins IgA and IgG, was measured by an enzyme-linked immunosorbent assay. Urinary excretion of albumin decreased dose-dependently (p < 0.05) 96 h post-injection relative to the control group. In contrast, no statistically significant effects were observed for other proteins tested. The dose-dependent decrease in urinary excretion of albumin observed in this study underscores the need for further research, which may lead to the discovery of new biomarkers that would reflect the changes in the primary target organs for deposition of (210)Po. PMID:26961776

  8. Safety of Intravitreally Administered Recombinant Erythropoietin (An AOS Thesis)

    PubMed Central

    Tsai, James C.

    2008-01-01

    Purpose This study investigated the safety and potential retinal toxicity of intravitreally administered erythropoietin (EPO) in a rodent animal model. Methods Forty-two healthy Sprague-Dawley rats were divided into one of 7 groups (N = 6 per group): control, sham injection, vehicle injection, and EPO injections of 50 ng (5 U), 100 ng (10 U), 250 ng (25 U), and 625 ng (62.5 U). Only the right eye was treated in each animal. Standard full-field dark- and light-adapted electroretinography (ERG) was obtained at 1 day prior to injection and then on postinjection days 3, 7, 14, and 21. Intraocular pressure (IOP) was measured at the conclusion of each ERG recording. Animals were sacrificed and the eyes underwent histologic examination with light microscopy and hematoxylin-eosin staining. Results Rod peak, scotopic, and photopic responses (amplitude and latency) were not statistically different in the animals receiving 50 to 100 ng EPO. In the 250-ng group, the photopic b-wave amplitude at day 21 was elevated (P <.05), whereas in the 625-ng group, the scotopic OP3 latency ratio was higher at baseline (P <.05). No significant histologic abnormalities were noted except for one animal (625-ng group) with qualitative differences in retinal layer thickness and cellular density. Conclusions Intravitreal administration of EPO (at doses up to 625 ng) does not cause adverse effects on retinal function as assessed by ERG. Moreover, single intravitreal dosing does not appear to elicit retinal neovascularization. Further investigation is warranted to assess fully the potential of this neuroprotective cytokine as a treatment for glaucoma. PMID:19277250

  9. [The effect of aldosterone A on renal potassium excretion].

    PubMed

    Winther, Signe Abitz; Egfjord, Martin

    2011-01-10

    Recent studies have shown expression of the following regulatory WNK kinases in the kidney: the full-length WNK1 (L-WNK1), the shorter kidney specific WNK1 transcript (KS-WNK1), formed by alternative splicing, and WNK4. Aldosterone activates expression of KS-WNK1 and inhibits WNK4 via SGK1 - both leading to stimulation of ENaC and activation of ROMK, and increased potassium excretion. Thus, further characterization of the WNK system may lead to elucidation of the dual anti-natriuretic and kaliuretic effects of aldosterone, in situations where only activation of one of these effects is needed. PMID:21219845

  10. Testosterone urinary excretion rate increases during hypergravity in male monkeys

    NASA Technical Reports Server (NTRS)

    Strollo, F.; Barger, L.; Fuller, C.

    2000-01-01

    Real and simulated microgravity impairs T secretion both in animals and in the human. To verify whether hypergravity might enhance T secretion as a consequence of an opposite mechanical effect, 6 male monkeys were centrifuged at 2 G for 3 weeks after a 1 G stabilization period lasting 3 weeks and then taken back to 1 G for 1 week and urine were collected daily for T excretion measurement. Significantly higher level were observed during the initial 2 G phase as compared to pre- and post centrifugation periods and the trend was the same during the remaining 2 G period. This may reflect changes in testicular perfusion rather than endocrine adaptation per se.

  11. Pharmacokinetics: metabolism and renal excretion of quinolones in man.

    PubMed

    Vree, T B; Wijnands, W J; Guelen, P J; Baars, A M; Hekster, Y A

    1986-02-21

    The quinolones are relatively poorly absorbed from the gastrointestinal tract. The elimination proceeds mainly by renal excretion. The half-life of elimination depends on the molecular structure and varies between 2 and 10 h. Impaired kidney function is expected to increase the half-life of elimination, though this effect is not always observed. Since the 4-oxo-metabolites show a higher renal clearance than the parent drug, renal impairment will result in a cumulation of the metabolites in the body. PMID:3960691

  12. Opicapone: a short lived and very long acting novel catechol-O-methyltransferase inhibitor following multiple dose administration in healthy subjects

    PubMed Central

    Rocha, José Francisco; Almeida, Luis; Falcão, Amílcar; Palma, P Nuno; Loureiro, Ana I; Pinto, Roberto; Bonifácio, Maria João; Wright, Lyndon C; Nunes, Teresa; Soares-da-Silva, Patrício

    2013-01-01

    Aims The aim of this study was to assess the tolerability, pharmacokinetics and inhibitory effect on erythrocyte soluble catechol-O-methyltransferase (S-COMT) activity following repeated doses of opicapone. Methods This randomized, placebo-controlled, double-blind study enrolled healthy male subjects who received either once daily placebo or opicapone 5, 10, 20 or 30 mg for 8 days. Results Opicapone was well tolerated. Its systemic exposure increased in an approximately dose-proportional manner with an apparent terminal half-life of 1.0 to 1.4 h. Sulphation was the main metabolic pathway. Opicapone metabolites recovered in urine accounted for less than 3% of the amount of opicapone administered suggesting that bile is likely the main route of excretion. Maximum S-COMT inhibition (Emax) ranged from 69.9% to 98.0% following the last dose of opicapone. The opicapone-induced S-COMT inhibition showed a half-life in excess of 100 h, which was dose-independent and much longer than plasma drug exposure. Such a half-life translates into a putative underlying rate constant that is comparable with the estimated dissociation rate constant of the COMT–opicapone complex. Conclusion Despite its short elimination half-life, opicapone markedly and sustainably inhibited erythrocyte S-COMT activity making it suitable for a once daily regimen. PMID:23336248

  13. Who Should Administer Energy-Efficiency Programs?

    SciTech Connect

    Blumstein, Carl; Goldman, Charles; Barbose, Galen L.

    2003-05-01

    The restructuring of the electric utility industry in the US created a crisis in the administration of ratepayer-funded energy-efficiency programs. Before restructuring, nearly all energy-efficiency programs in the US were administered by utilities and funded from utility rates. Restructuring called these arrangements into question in two ways. First, the separation of generation from transmission and distribution undermined a key rationale for utility administration. This was the Integrated Resource Planning approach in which the vertically integrated utility was given incentives to provide energy services at least cost. Second, questions were raised as to whether funding through utility rates could be sustained in a competitive environment and most states that restructured their electricity industry adopted a system benefits charge. The crisis in administration of energy-efficiency programs produced a variety of responses in the eight years since restructuring in the US began in earn est. These responses have included new rationales for energy-efficiency programs, new mechanisms for funding programs, and new mechanisms for program administration and governance. This paper focuses on issues related to program administration. It describes the administrative functions and some of the options for accomplishing them. Then it discusses criteria for choosing among the options. Examples are given that highlight some of the states that have made successful transitions to new governance and/or administration structures. Attention is also given to California where large-scale energy-efficiency programs have continued to operate, despite the fact that many of the key governance/administration issues remain unresolved. The conclusion attempts to summarize lessons learned.

  14. Single- and multiple-dose tolerability and pharmacokinetics of the CRTH2 antagonist setipiprant in healthy male subjects.

    PubMed

    Sidharta, Patricia N; Diamant, Zuzana; Dingemanse, Jasper

    2014-12-01

    Chemoattractant receptor-homologous molecule expressed on T helper (Th) 2 cells (CRTH2) is a G-protein-coupled receptor for prostaglandin D2 (PGD2), a key mediator in inflammatory disorders such as asthma and allergic rhinitis. In this study, we investigated the single- and multiple-dose tolerability and pharmacokinetics (PKs) of setipiprant, an orally active, potent, and selective CRTH2 antagonist. This randomized, double-blind, placebo-controlled study was performed in two parts in healthy male subjects. In study Part A, single oral doses of up to 2000 mg setipiprant or placebo were given to sequential groups of eight subjects each. Additionally, the impact of food on the PKs was investigated in one-dose group. In study Part B, two groups of subjects received 500 or 1000 mg setipiprant or placebo b.i.d. during 5.5 days. At regular intervals, tolerability variables and plasma and urine levels of setipiprant were determined. Setipiprant was well tolerated after single- and multiple-dose administration. Headache was the most frequently reported adverse event. No treatment effect on tolerability variables was observed. After single- and multiple-dose administration, setipiprant was rapidly absorbed and followed a biphasic elimination pattern with an elimination half-life between 10 and 18 h. Steady-state conditions were reached after 2-3 days and setipiprant did not accumulate. Exposure to setipiprant was lower in the presence of food. Urinary excretion of unchanged setipiprant did not exceed 7% of the administered dose. In this entry-into-human study, setipiprant showed good tolerability and a favorable PK profile, thus warranting its development in the treatment of inflammatory disorders. PMID:24734908

  15. EFFECTS OF DOSE AND ROUTE OF EXPOSURE ON DIOXIN DISPOSITION

    EPA Science Inventory

    The absorption, distribution, metabolism and excretion of 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) was studied in male F344 rats. ral absorption was dose-dependent. bsorption of 1 nmol/kg by both the oral and intratracheal (itr) routes was -80%, whereas only -12% was absorbed th...

  16. Effects of Systemically Administered Hydrocortisone on the Human Immunome.

    PubMed

    Olnes, Matthew J; Kotliarov, Yuri; Biancotto, Angélique; Cheung, Foo; Chen, Jinguo; Shi, Rongye; Zhou, Huizhi; Wang, Ena; Tsang, John S; Nussenblatt, Robert

    2016-01-01

    Corticosteroids have been used for decades to modulate inflammation therapeutically, yet there is a paucity of data on their effects in humans. We examined the changes in cellular and molecular immune system parameters, or "immunome", in healthy humans after systemic corticosteroid administration. We used multiplexed techniques to query the immunome in 20 volunteers at baseline, and after intravenous hydrocortisone (HC) administered at moderate (250 mg) and low (50 mg) doses, to provide insight into how corticosteroids exert their effects. We performed comprehensive phenotyping of 120 lymphocyte subsets by high dimensional flow cytometry, and observed a decline in circulating specific B and T cell subsets, which reached their nadir 4-8 hours after administration of HC. However, B and T cells rebounded above baseline 24 hours after HC infusion, while NK cell numbers remained stable. Whole transcriptome profiling revealed down regulation of NF-κB signaling, apoptosis, and cell death signaling transcripts that preceded lymphocyte population changes, with activation of NK cell and glucocorticoid receptor signaling transcripts. Our study is the first to systematically characterize the effects of corticosteroids on the human immunome, and we demonstrate that HC exerts differential effects on B and T lymphocytes and natural killer cells in humans. PMID:26972611

  17. Inducing and Administering Tregs to Treat Human Disease

    PubMed Central

    Perdigoto, Ana Luisa; Chatenoud, Lucienne; Bluestone, Jeffrey A.; Herold, Kevan C.

    2016-01-01

    Regulatory T cells (Tregs) control unwanted immune responses, including those that mediate tolerance to self as well as to foreign antigens. Their mechanisms of action include direct and indirect effects on effector T cells and important functions in tissue repair and homeostasis. Tregs express a number of cell surface markers and transcriptional factors that have been instrumental in defining their origins and potentially their function. A number of immune therapies, such as rapamycin, IL-2, and anti-T cell antibodies, are able to induce Tregs and are being tested for their efficacy in diverse clinical settings with exciting preliminary results. However, a balance exists with the use of some, such as IL-2, that may have effects on unwanted populations as well as promoting expansion and survival of Tregs requiring careful selection of dose for clinical use. The use of cell surface markers has enabled investigators to isolate and expand ex vivo Tregs more than 500-fold routinely. Clinical trials have begun, administering these expanded Tregs to patients as a means of suppressing autoimmune and alloimmune responses and potentially inducing immune tolerance. Studies in the future are likely to build on these initial technical achievements and use combinations of agents to improve the survival and functional capacity of Tregs. PMID:26834735

  18. Effects of Systemically Administered Hydrocortisone on the Human Immunome

    PubMed Central

    Olnes, Matthew J.; Kotliarov, Yuri; Biancotto, Angélique; Cheung, Foo; Chen, Jinguo; Shi, Rongye; Zhou, Huizhi; Wang, Ena; Tsang, John S.; Nussenblatt, Robert; Dickler, Howard B.; Hourigan, Christopher S.; Marincola, Francesco M.; McCoy, J. Phillip; Perl, Shira; Schum, Paula; Schwartzberg, Pamela L.; Trinchieri, Giorgio; Valdez, Janet; Young, Neal S.

    2016-01-01

    Corticosteroids have been used for decades to modulate inflammation therapeutically, yet there is a paucity of data on their effects in humans. We examined the changes in cellular and molecular immune system parameters, or “immunome”, in healthy humans after systemic corticosteroid administration. We used multiplexed techniques to query the immunome in 20 volunteers at baseline, and after intravenous hydrocortisone (HC) administered at moderate (250 mg) and low (50 mg) doses, to provide insight into how corticosteroids exert their effects. We performed comprehensive phenotyping of 120 lymphocyte subsets by high dimensional flow cytometry, and observed a decline in circulating specific B and T cell subsets, which reached their nadir 4–8 hours after administration of HC. However, B and T cells rebounded above baseline 24 hours after HC infusion, while NK cell numbers remained stable. Whole transcriptome profiling revealed down regulation of NF-κB signaling, apoptosis, and cell death signaling transcripts that preceded lymphocyte population changes, with activation of NK cell and glucocorticoid receptor signaling transcripts. Our study is the first to systematically characterize the effects of corticosteroids on the human immunome, and we demonstrate that HC exerts differential effects on B and T lymphocytes and natural killer cells in humans. PMID:26972611

  19. Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects.

    PubMed

    Song, Ivy; Borland, Julie; Arya, Niki; Wynne, Brian; Piscitelli, Stephen

    2015-05-01

    All commercially available integrase inhibitors are 2-metal binders and may be affected by co-administration with metal cations. The purpose of this study was to evaluate the effect of calcium and iron supplements on dolutegravir pharmacokinetics and strategies (dose separation and food) to attenuate the effects if significant reductions in dolutegravir exposure were observed. This was an open-label, crossover study that randomized 24 healthy subjects into 1 of 2 cohorts to receive 4 treatments: (1) dolutegravir alone, fasting; (2) dolutegravir with calcium carbonate or ferrous fumarate, fasting; (3) dolutegravir with calcium carbonate or ferrous fumarate with a moderate-fat meal; (4) dolutegravir administered 2 hours before calcium carbonate or ferrous fumarate, fasting. Plasma dolutegravir AUC(0-∞), Cmax , and C24 were reduced by 39%, 37%, and 39%, respectively, when co-administered with calcium carbonate while fasting and were reduced by 54%, 57%, and 56%, respectively, when co-administered with ferrous fumarate while fasting. Dolutegravir administration 2 hours before calcium or iron supplement administration (fasted), as well as administration with a meal, counteracted the effect. Dolutegravir and calcium or iron supplements can be co-administered if taken with a meal. Under fasted conditions, dolutegravir should be administered 2 hours before or 6 hours after calcium or iron supplements. PMID:25449994

  20. Early Biochemical Effects of an Organic Mercury Fungicide on Infants: ``Dose Makes the Poison''

    NASA Astrophysics Data System (ADS)

    Gotelli, Carlos A.; Astolfi, Emilio; Cox, Christopher; Cernichiari, Elsa; Clarkson, Thomas W.

    1985-02-01

    Phenylmercury absorbed through the skin from contaminated diapers affected urinary excretion in infants in Buenos Aires. The effects were reversible and quantitatively related to the concentration of urinary mercury. Excretion of γ -glutamyl transpeptidase, an enzyme in the brush borders of renal tubular cells, increased in a dose-dependent manner when mercury excretion exceeded a ``threshold'' value. Urine volume also increased but at a higher threshold with respect to mercury. The results support the threshold concept of the systemic toxicity of metals. γ -Glutamyl transpeptidase is a useful and sensitive marker for preclinical effects of toxic metals.

  1. Effect of centrally administered losartan on gastric and duodenal ulcers in rats.

    PubMed

    Merai, Ankitkumar Harshadrai; Asad, Mohammed; Prasad, V Satya

    2009-01-01

    The effect of centrally administered losartan, an AT(1) receptor antagonist, on gastric acid secretion and gastric cytoprotection was studied using different models of gastric ulcers, such as acetic acid-induced chronic gastric ulcers, pylorus ligation, ethanol-induced and stress-induced acute gastric ulcers and cysteamine hydrochloride-induced duodenal ulcer. Losartan was administered intracerebroventrically (i.c.v.) at 2 different doses (125 and 250 microg/kg). Both doses of losartan increased the healing of acetic acid-induced chronic gastric ulcers. In pylorus-ligated rats, a significant reduction in free acidity, total acidity and ulcer index was observed with high dose (250 microg/kg, i.c.v.), while low dose (125 microg/kg, i.c.v.) produced reduction only in free acidity and ulcer index. Both doses also produced a significant antiulcer effect in ethanol-induced and stress-induced gastric ulcers. Losartan also reduced ulcer area in cysteamine-induced duodenal ulcer. We conclude that AT(1) receptor antagonism in the brain increases healing of gastric ulcers and reduces gastric acid secretion and increases gastric mucin content. PMID:19602912

  2. Excretion of iodine-123-hippuran, technetium-99m-red blood cells, and technetium-99m-macroaggregated albumin into breast milk

    SciTech Connect

    Rose, M.R.; Prescott, M.C.; Herman, K.J. )

    1990-06-01

    The amount of radioactivity excreted in breast milk following three different nuclear medicine procedures on twelve nursing mothers has been measured. Some of this information has already been incorporated into the latest guidelines on suspension of feeding after maternal radiopharmaceutical administration. The overall radiation dose that the patients' babies would have sustained had breast feeding not been interrupted has been estimated as an effective dose equivalent. A model has been developed to describe the relationship between clearance of activity from the milk, time between expressions, and the fraction of milk expressed. Some simple guidance is given on calculation of suitable interruption times for any individual mother from counts on her milk samples.

  3. Pharmacokinetics, tissue distribution and excretion study of a furostanol glycoside-based standardized fenugreek seed extract in rats.

    PubMed

    Kandhare, Amit D; Bodhankar, Subhash L; Mohan, V; Thakurdesai, Prasad A

    2015-08-01

    The furostanol glycoside isolated from the seed of fenugreek (SFSE-G) has an array of pharmacological activities. To date, no validated high-performance liquid chromatography (HPLC) method has been reported for quantification of SFSE-G in biological samples. Hence, the aim of the present study was to study the pharmacokinetics, tissue distribution and excretion profiles of SFSE-G after oral administration in rats. A rapid, sensitive, selective, robust and reproducible HPLC method has been developed for determination of SFSE-G in the rat biological samples. The chromatographic separation was accomplished on a reversed-phase C18 column using formic acid and acetonitrile (80:20) as mobile phase at a flow rate of 1.0 mL/min and 274 nm as a detection wavelength. The assay was linear for SFSE-G with the correlation coefficients (R(2)) >0.996. The analytes were stable during samples storage and handling, and no matrix effects were observed. After oral dosing of SFSE-G at a dose of 200 mg/kg, the elimination half-life was app. 40.10 h. It showed relatively slowly distribution and eliminated in urine and feces after 24 h, and could be detected until 108 h post-dosing. Following oral single dose (200 mg/kg), SFSE-G was detected in lung and brain which indicated that it could cross the blood-brain barrier. It is a major route of elimination is excretion through urine and feces. In conclusion, oral administration of SFSE-G showed slow distribution to tissues, such as lung and brain, but showed fast renal elimination. PMID:26104039

  4. Estimated dose rates to members of the public from external exposure to patients with 131I thyroid treatment

    DOE PAGESBeta

    Dewji, S.; Bellamy, M.; Hertel, N.; Leggett, R.; Sherbini, S.; Saba, M.; Eckerman, K.

    2015-03-25

    The purpose of this study is to estimate dose rates that may result from exposure to patients who had been administered iodine-131 (131I) as part of medical therapy were calculated. These effective dose rate estimates were compared with simplified assumptions under United States Nuclear Regulatory Commission Regulatory Guide 8.39, which does not consider body tissue attenuation nor time-dependent redistribution and excretion of the administered 131I. Methods: Dose rates were estimated for members of the public potentially exposed to external irradiation from patients recently treated with 131I. Tissue attenuation and iodine biokinetics were considered in the patient in a larger comprehensivemore » effort to improve external dose rate estimates. The external dose rate estimates are based on Monte Carlo simulations using the Phantom with Movable Arms and Legs (PIMAL), previously developed by Oak Ridge National Laboratory and the United States Nuclear Regulatory Commission. PIMAL was employed to model the relative positions of the 131I patient and members of the public in three exposure scenarios: (1) traveling on a bus in a total of six seated or standing permutations, (2) two nursing home cases where a caregiver is seated at 30 cm from the patient’s bedside and a nursing home resident seated 250 cm away from the patient in an adjacent bed, and (3) two hotel cases where the patient and a guest are in adjacent rooms with beds on opposite sides of the common wall, with the patient and guest both in bed and either seated back-to-back or lying head to head. The biokinetic model predictions of the retention and distribution of 131I in the patient assumed a single voiding of urinary bladder contents that occurred during the trip at 2, 4, or 8 h after 131I administration for the public transportation cases, continuous first-order voiding for the nursing home cases, and regular periodic voiding at 4, 8, or 12 h after administration for the hotel room cases. Organ

  5. Estimated dose rates to members of the public from external exposure to patients with {sup 131}I thyroid treatment

    SciTech Connect

    Dewji, S. Bellamy, M.; Leggett, R.; Eckerman, K.; Hertel, N.; Sherbini, S.; Saba, M.

    2015-04-15

    Purpose: Estimated dose rates that may result from exposure to patients who had been administered iodine-131 ({sup 131}I) as part of medical therapy were calculated. These effective dose rate estimates were compared with simplified assumptions under United States Nuclear Regulatory Commission Regulatory Guide 8.39, which does not consider body tissue attenuation nor time-dependent redistribution and excretion of the administered {sup 131}I. Methods: Dose rates were estimated for members of the public potentially exposed to external irradiation from patients recently treated with {sup 131}I. Tissue attenuation and iodine biokinetics were considered in the patient in a larger comprehensive effort to improve external dose rate estimates. The external dose rate estimates are based on Monte Carlo simulations using the Phantom with Movable Arms and Legs (PIMAL), previously developed by Oak Ridge National Laboratory and the United States Nuclear Regulatory Commission. PIMAL was employed to model the relative positions of the {sup 131}I patient and members of the public in three exposure scenarios: (1) traveling on a bus in a total of six seated or standing permutations, (2) two nursing home cases where a caregiver is seated at 30 cm from the patient’s bedside and a nursing home resident seated 250 cm away from the patient in an adjacent bed, and (3) two hotel cases where the patient and a guest are in adjacent rooms with beds on opposite sides of the common wall, with the patient and guest both in bed and either seated back-to-back or lying head to head. The biokinetic model predictions of the retention and distribution of {sup 131}I in the patient assumed a single voiding of urinary bladder contents that occurred during the trip at 2, 4, or 8 h after {sup 131}I administration for the public transportation cases, continuous first-order voiding for the nursing home cases, and regular periodic voiding at 4, 8, or 12 h after administration for the hotel room cases. Organ

  6. Pharmacodynamics of oxytetracycline administered alone and in combination with carprofen in calves.

    PubMed

    Brentnall, C; Cheng, Z; McKellar, Q A; Lees, P

    2012-09-15

    The pharmacodynamics (PD) of oxytetracycline was investigated against a strain of Mannheimia haemolytica. In vitro measurements, comprising minimum inhibitory concentration (MIC), minimum bactericidal concentration and time-kill curves, were conducted in five matrices; Mueller Hinton Broth (MHB), cation-adjusted MHB (CAMHB) and calf serum, exudate and transudate. MICs were much higher in the biological fluids than in MHB and CAMHB. Ratios of MIC were, serum: CAMHB 19 : 1; exudate:CAMHB 16.1; transudate:CAMHB 14 : 1. Ex vivo data, generated in the tissue cage model of inflammation, demonstrated that oxytetracycline, administered to calves intramuscularly at a dose rate of 20 mg/kg, did not inhibit the growth of M haemolytica in serum, exudate and transudate, even at peak concentration. However, using in vitro susceptibility in CAMHB and in vivo-determined pharmacokinetic (PK) variables, average and minimum oxytetracycline concentrations relative to MIC (C(av)/MIC and C(min)/MIC) predicted achievement of efficacy for approximately 48 hours after dosing. Similar C(av)/MIC and C(min)/MIC data were obtained when oxytetracycline was administered in the presence of carprofen. PK-PD integration of data for oxytetracycline, based on MICs determined in the three biological fluids, suggests that it possesses, at most, limited direct killing activity against M haemolytica. These data raise questions concerning the mechanism(s) of action of oxytetracycline, when administered at clinically recommended dose rates. PMID:22843613

  7. Rapid Hepatobiliary Excretion of Micelle-Encapsulated/Radiolabeled Upconverting Nanoparticles as an Integrated Form

    PubMed Central

    Seo, Hyo Jung; Nam, Sang Hwan; Im, Hyung-Jun; Park, Ji-yong; Lee, Ji Youn; Yoo, Byeongjun; Lee, Yun-Sang; Jeong, Jae Min; Hyeon, Taeghwan; Who Kim, Ji; Lee, Jae Sung; Jang, In-Jin; Cho, Joo-Youn; Hwang, Do Won; Suh, Yung Doug; Lee, Dong Soo

    2015-01-01

    In the field of nanomedicine, long term accumulation of nanoparticles (NPs) in the mononuclear phagocyte system (MPS) such as liver is the major hurdle in clinical translation. On the other hand, NPs could be excreted via hepatobiliary excretion pathway without overt tissue toxicity. Therefore, it is critical to develop NPs that show favorable excretion property. Herein, we demonstrated that micelle encapsulated 64Cu-labeled upconverting nanoparticles (micelle encapsulated 64Cu-NOTA-UCNPs) showed substantial hepatobiliary excretion by in vivo positron emission tomography (PET) and also upconversion luminescence imaging (ULI). Ex vivo biodistribution study reinforced the imaging results by showing clearance of 84% of initial hepatic uptake in 72 hours. Hepatobiliary excretion of the UCNPs was also verified by transmission electron microscopy (TEM) examination. Micelle encapsulated 64Cu-NOTA-UCNPs could be an optimal bimodal imaging agent owing to quantifiability of 64Cu, ability of in vivo/ex vivo ULI and good hepatobiliary excretion property. PMID:26494465

  8. The significance of nitrate in the nitrogenous excretion of carcinus maenas

    NASA Astrophysics Data System (ADS)

    Spaargaren, D. H.

    Total inorganic-N and NH 4+-N were measured in blood and external media of shore crabs, Carcinus maenas (L.), exposed to various salinities at low (4°C) and high (20°C) temperatures. Total inorganic-N and NH 4+-N were both excreted in larger amounts at lower salinities and at the higher temperature. Nitrate excretion is highest in brackish water and decreases in both higher and lower salinities. Nitrate excretion (0.11-0.72 μmol -1·h -1) was of the same order of magnitude as NH 4 + excretion, but in brackish water NO 3 - excretion predominated, whereas at lower salinities NH 4 + excretion predominated. NO 3 - formation may serve in the detoxification of NH 4 + and the maintenance of electroneutrality. Blood NO 3 - concentrations, like blood NH 4 + concentrations, are strongly stabilized, independent of either temperature or salinity.

  9. Evaluation of the prenatal developmental toxicity of orally administered arsenic trioxide in rats.

    PubMed

    Holson, J F; Stump, D G; Clevidence, K J; Knapp, J F; Farr, C H

    2000-05-01

    A thorough review of the literature revealed no published repeated-dose oral developmental toxicity studies of inorganic arsenic in rats. In the present study, which was conducted according to modern regulatory guidelines, arsenic trioxide was administered orally beginning 14 days prior to mating and continuing through mating and gestation until gestational day 19. Exposures began prior to mating in an attempt to achieve a steady state of arsenic in the bloodstream of dams prior to embryo-foetal development. Groups of 25 Crl:CD(SD)BR female rats received doses of 0, 1, 2.5, 5 or 10mg/kg/day by gavage. The selection of these dose levels was based on a preliminary range-finding study, in which excessive post-implantation loss and markedly decreased foetal weight occurred at doses of 15 mg/kg/day and maternal deaths occurred at higher doses. Maternal toxicity in the 10mg/kg/day group was evidenced by decreased food consumption and decreased net body weight gain during gestation, increased liver and kidney weights, and stomach abnormalities (adhesions and eroded areas). Transient decreases in food consumption in the 5mg/kg/day group caused the maternal no-observed-adverse-effect level (NOAEL) to be determined as 2. 5mg/kg/day. Intrauterine parameters were unaffected by arsenic trioxide. No treatment-related foetal malformations were noted in any dose group. Increased skeletal variations at 10mg/kg/day were attributed to reduced foetal weight at that dose level. The developmental NOAEL was thus 5mg/kg/day. Based on this study, orally administered arsenic trioxide cannot be considered to be a selective developmental toxicant (i.e. it is not more toxic to the conceptus than to the maternal organism), nor does it exhibit any propensity to cause neural tube defects, even at maternally toxic dose levels. PMID:10762732

  10. [Basic mechanisms: absorption and excretion of cholesterol and other sterols].

    PubMed

    Cofan Pujol, Montserrat

    2014-01-01

    Cholesterol is of vital importance for vertebrate cell membrane structure and function. It is obvious that adequate regulation of cholesterol homeostasis is essential. Hypercholesterolemia promotes atherosclerosis and thereby represents a major risk factor for cardiovascular disease. The liver has been considered the major site of control in maintenance of cholesterol homeostasis. The liver facilitates clearance of (very) low density lipoprotein particles and cholesterol-containing chylomicron remnants, synthesizes cholesterol, synthesizes and secretes (nascent) high density lipoprotein particles, secretes cholesterol and bile salts to bile, and is involved in reverse cholesterol transport. In recent years, however, the importance of the intestine in many aspects of cholesterol physiology is increasingly recognized. It has become apparent that direct secretion of cholesterol from the blood compartment into the intestine, or transintestinal cholesterol excretion, plays a major role in disposal of cholesterol via the feces. This review will discuss current knowledge on the physiology of cholesterol homeostasis, with emphasis on cholesterol absorption, cholesterol synthesis and fecal excretion, and therapeutic options for hypercholesterolemia. PMID:24461630

  11. Enhancement of anammox by the excretion of diel vertical migrators

    NASA Astrophysics Data System (ADS)

    Bianchi, Daniele; Babbin, Andrew R.; Galbraith, Eric D.

    2014-11-01

    Measurements show that anaerobic ammonium oxidation with nitrite (anammox) is a major pathway of fixed nitrogen removal in the anoxic zones of the open ocean. Anammox requires a source of ammonium, which under anoxic conditions could be supplied by the breakdown of sinking organic matter via heterotrophic denitrification. However, at many locations where anammox is measured, denitrification rates are small or undetectable. Alternative sources of ammonium have been proposed to explain this paradox, for example through dissimilatory reduction of nitrate to ammonium and transport from anoxic sediments. However, the relevance of these sources in open-ocean anoxic zones is debated. Here, we bring to attention an additional source of ammonium, namely, the daytime excretion by zooplankton and micronekton migrating from the surface to anoxic waters. We use a synthesis of acoustic data to show that, where anoxic waters occur within the water column, most migrators spend the daytime within them. Although migrators export only a small fraction of primary production from the surface, they focus excretion within a confined depth range of anoxic water where particle input is small. Using a simple biogeochemical model, we suggest that, at those depths, the source of ammonium from organisms undergoing diel vertical migrations could exceed the release from particle remineralization, enhancing in situ anammox rates. The contribution of this previously overlooked process, and the numerous uncertainties surrounding it, call for further efforts to evaluate the role of animals in oxygen minimum zone biogeochemistry.

  12. Retention and excretion of 95Zr-95Nb in humans.

    PubMed

    Thind, K S

    1995-12-01

    This note describes the retention and excretion of 95Zr-95Nb in humans based on a recent CANDU experience and a literature survey of reported cases. Two data bases, QUEST and INIS were used for the survey. Three reported cases were discovered: two for occupational exposures and one for public exposure from nuclear weapons fallout. Human lung retention from these three cases, plus whole body retention and some limited fecal excretion data from a recently occurred exposure at a CANDU station, were reviewed and tested against predictions based on ICRP Publication 30 model. Based on the fits of this model to the reported data it seems that the three occupational exposures exhibit class Y behavior while the public exposure exhibits class W behavior. For only one case is the chemical compound known with certainty: ZrO2. Zirconium oxides are currently classified as class W in ICRP Publications 30 and 54. This work confirms a suggestion that oxides of zirconium be classified as class Y and should be taken into account by the ICRP in its future publications. PMID:7493813

  13. High Salt Diet Affects Renal Sodium Excretion and ERRα Expression

    PubMed Central

    Wang, Dan; Wang, Yang; Liu, Fu-Qiang; Yuan, Zu-Yi; Mu, Jian-Jun

    2016-01-01

    Kidneys regulate the balance of water and sodium and therefore are related to blood pressure. It is unclear whether estrogen-related receptor α (ERRα), an orphan nuclear receptor and transcription factor highly expressed in kidneys, affects the reabsorption of water and sodium. The aim of this study was to determine whether changes in the expressions of ERRα, Na+/K+-ATPase and epithelial sodium channel (ENaC) proteins affected the reabsorption of water and sodium in kidneys of Dahl salt-sensitive (DS) rats. SS.13BN rats, 98% homologous to the DS rats, were used as a normotensive control group. The 24 h urinary sodium excretion of the DS and SS.13BN rats increased after the 6-week high salt diet intervention, while sodium excretion was increased in DS rats with daidzein (agonist of ERRα) treatment. ERRα expression was decreased, while β- and γ-ENaC mRNA expressions were increased upon high sodium diet treatment in the DS rats. In the chromatin immunoprecipitation (CHIP) assay, positive PCR signals were obtained in samples treated with anti-ERRα antibody. The transcriptional activity of ERRα was decreased upon high salt diet intervention. ERRα reduced the expressions of β- and γ-ENaC by binding to the ENaC promoter, thereby increased Na+ reabsorption. Therefore, ERRα might be one of the factors causing salt-sensitive hypertension. PMID:27043552

  14. Metabolism and Excretion of Trichloroethylene after Inhalation by Human Subjects

    PubMed Central

    Bartoníček, V.

    1962-01-01

    Eight volunteers were exposed to trichloroethylene vapour (1,042 μg./l.) for five hours; 51 to 64% of the inhaled trichloroethylene was retained. The concentration of trichloroethanol and trichloroacetic acid in the urine was studied daily for a three-week period; on the third day both metabolites were determined in faeces, sweat, and saliva. The concentration of trichloroacetic acid in plasma and red blood cells was studied on alternate days. Of the trichloroethylene retained, 38·0 to 49·7% was excreted in the urine as trichloroethanol and 27·4 to 35·7% as trichloroacetic acid. Of both metabolites 8·4% was excreted in the faeces. Sweat collected on the third day of the experiment contained 0·10 to 1·92 mg./100 ml. trichloroethanol and 0·15 to 0·35 mg./100 ml. trichloroacetic acid. In saliva the concentrations were 0·09 to 0·32 mg./100 ml. trichloroethanol and 0·10 to 0·15 mg./100 ml. trichloroacetic acid. The value of the expression trichloroethanol/trichloroacetic acid calculated in the urine within 22 days was within the range 1·15 to 1·81. PMID:13865497

  15. Possible parameters in the urinary excretion of tritium

    SciTech Connect

    Cawley, C.N.; Lewis, B.A.; Cannon, L.A.

    1985-11-01

    Because of its mobility in both physical and biological systems, tritium is interesting both as a tracer and as an issue in health physics. Because tritium is extremely difficult to contain, it is one of the major radionuclides of concern if released to the environment from nuclear facilities. Relatively very large releases are tolerated because the beta particle has low energy and, therefore, the radioisotope is not a health hazard unless deposited internally. Moreover, on release to the environment, tritium enters the hydrologic cycle and is diluted and dispersed widely through the hydrosphere. It is likely that tritium uptake and loss in humans is more complex than generally believed and may be more functionally related to physiological processes, such as the bicarbonate and electrolyte balances, than to ambient environmental conditions such as temperature. Despite the many uncertainties in the analyses of experimental data on tritium contamination and excretion, it is likely that further investigations will establish both a better understanding of the tritium health hazard and the physiological processes governing excretion and, perhaps, its indefinite recycling through metabolic pools.

  16. Metabolism and urinary excretion kinetics of di(2-ethylhexyl) terephthalate (DEHTP) in three male volunteers after oral dosage.

    PubMed

    Lessmann, Frederik; Schütze, André; Weiss, Tobias; Langsch, Angelika; Otter, Rainer; Brüning, Thomas; Koch, Holger M

    2016-07-01

    Di(2-ethylhexyl) terephthalate (DEHTP) is used as a substitute for di(2-ethylhexyl) phthalate (DEHP), an ortho-phthalate-based plasticizer that is classified and labeled due to its toxicity to reproduction. In this study the metabolism and urinary excretion kinetics of DEHTP were investigated by single oral dosage of 50 mg DEHTP to three male volunteers (resulting in individual dosages between 0.55 and 0.59 mg/kg body weight). Separate urine samples were consecutively collected for 48 h. In analogy to DEHP, we quantified specific side-chain-oxidized monoester metabolites of DEHTP (5OH-MEHTP, 5oxo-MEHTP, 5cx-MEPTP and 2cx-MMHTP) by HPLC-MS/MS with online sample clean-up and isotope dilution. All postulated metabolites were detectable in all samples after dosage. The predominant, specific urinary metabolite was 5cx-MEPTP representing about 13.0 % of the applied dose as mean of the three volunteers (range 7.0-20.4 %) in urine, followed by 5OH-MEHTP (mean: 1.8 %; range 1.3-2.4 %) and 5oxo MEHTP (mean: 1.0 %; range 0.6-1.6 %). 2cx-MMHTP was a minor metabolite representing only 0.3 % (range 0.2-0.4 %). In total, about 16.1 % of the dose was recovered in urine as the above investigated specific metabolites within 48 h with the major share (95 %) being excreted within the first 24 h. Investigation of the glucuronidation patterns revealed that the carboxy-metabolites are excreted almost completely in their free form (>90 %), whereas for 5OH-MEHTP and 5oxo-MEHTP, glucuronidation is preferred (>70 %). With this study we provide reliable urinary excretion factors to calculate DEHTP intakes based on metabolite concentrations in environmental and occupational studies. PMID:27116293

  17. Effects of feeding and confinement on nitrogen metabolism and excretion in the gulf toadfish Opsanus beta

    PubMed

    Walsh; Milligan

    1995-01-01

    In order to elucidate further the cues for, and the biochemical mechanisms of, the transition to ureogenesis in the gulf toadfish Opsanus beta, experiments on the effects of feeding (i.e. nitrogen loading) were carried out. Baseline nitrogen excretion rates were first measured on solitary toadfish in large water volumes (i.e. unconfined conditions). These nitrogen excretion rates were higher, and had a higher proportion as ammonia (61 %), than previously published 'control' measurements. Feeding of unconfined toadfish elevated total nitrogen excretion approximately threefold, with little change in the proportion of urea versus ammonia. During the first 24 h of confinement of unfed toadfish, absolute levels of urea excretion remained constant while ammonia excretion rates fell to near zero, so that toadfish became 90 % ureotelic. When fed prior to confinement, urea excretion rates remained constant for the first 24 h, and the bulk of the nitrogen was excreted as ammonia (80 %); excretion of the excess dietary nitrogen took up to 48 h to complete. If pre-adapted to confinement and then fed, toadfish excreted only about 55 % of their nitrogenous waste as ammonia, and excretion of excess dietary nitrogen was completed by 24 h. Elevations of hepatic glutamine synthetase (GNS) activities accompanied confinement and were shown to be almost exclusively in the cytosolic compartment and to be correlated with a decrease in the ratio of hepatic levels of glutamate:glutamine. These GNS activity increases also appear to account in part for the decrease in the percentage of ammoniotely in toadfish under conditions of nitrogen loading after confinement. However, additional means of regulating total nitrogen excretion (e.g. changes in protein turnover rates) and the degree of ureogenesis versus ammoniogenesis (e.g. N-acetylglutamate stimulation of carbamoylphosphate synthetase) must be postulated to account fully for changes in nitrogen excretion rates and activation of ureogenesis

  18. [SKIERS URINARY CATECHOLAMINES EXCRETION AT REST AND BY COMPETITIVE LOADS LENGTH VARIETY].

    PubMed

    Chinkin, A S

    2015-11-01

    While night sleeps urinary noradrenaline excretion of skilled skiers less than their untrained peers, but the difference in excretion of adrenaline is not revealed. By increasing the distance and time to overcome it during skiing catecholamine excretion is increased both - totally and per minute. Most urinary catecholamines detected at a distance of 50 km in low sliding: increased excretion of adrenaline - 84 times, and noradrenaline -95 times. These results shows that high qualificated skier's functional reserve of the sympathoadrenal system, is mobilize at long competitions for ten times higher than in rest. PMID:26995960

  19. Patterns of Mycobacterium tuberculosis-complex excretion and characterization of super-shedders in naturally-infected wild boar and red deer.

    PubMed

    Santos, Nuno; Almeida, Virgílio; Gortázar, Christian; Correia-Neves, Margarida

    2015-01-01

    Wild boar (Sus scrofa) and red deer (Cervus elaphus) are the main maintenance hosts for bovine tuberculosis (bTB) in continental Europe. Understanding Mycobacterium tuberculosis complex (MTC) excretion routes is crucial to define strategies to control bTB in free-ranging populations, nevertheless available information is scarce. Aiming at filling this gap, four different MTC excretion routes (oronasal, bronchial-alveolar, fecal and urinary) were investigated by molecular methods in naturally infected hunter-harvested wild boar and red deer. In addition MTC concentrations were estimated by the Most Probable Number method. MTC DNA was amplified in all types of excretion routes. MTC DNA was amplified in at least one excretion route from 83.0% (CI95 70.8-90.8) of wild ungulates with bTB-like lesions. Oronasal or bronchial-alveolar shedding were detected with higher frequency than fecal shedding (p < 0.001). The majority of shedders yielded MTC concentrations <10(3) CFU/g or mL. However, from those ungulates from which oronasal, bronchial-alveolar and fecal samples were available, 28.2% of wild boar (CI95 16.6-43.8) and 35.7% of red deer (CI95 16.3-61.2) yielded MTC concentrations >10(3) CFU/g or mL (referred here as super-shedders). Red deer have a significantly higher risk of being super-shedders compared to wild boar (OR = 11.8, CI95 2.3-60.2). The existence of super-shedders among the naturally infected population of wild boar and red deer is thus reported here for the first time and MTC DNA concentrations greater than the minimum infective doses were estimated in excretion samples from both species. PMID:26518244

  20. Mathematical Modeling of Bacterial Kinetics to Predict the Impact of Antibiotic Colonic Exposure and Treatment Duration on the Amount of Resistant Enterobacteria Excreted

    PubMed Central

    Nguyen, Thu Thuy; Guedj, Jeremie; Chachaty, Elisabeth; de Gunzburg, Jean; Andremont, Antoine; Mentré, France

    2014-01-01

    Fecal excretion of antibiotics and resistant bacteria in the environment are major public health threats associated with extensive farming and modern medical care. Innovative strategies that can reduce the intestinal antibiotic concentrations during treatments are in development. However, the effect of lower exposure on the amount of resistant enterobacteria excreted has not been quantified, making it difficult to anticipate the impact of these strategies. Here, we introduce a bacterial kinetic model to capture the complex relationships between drug exposure, loss of susceptible enterobacteria and growth of resistant strains in the feces of piglets receiving placebo, 1.5 or 15 mg/kg/day ciprofloxacin, a fluoroquinolone, for 5 days. The model could well describe the kinetics of drug susceptible and resistant enterobacteria observed during treatment, and up to 22 days after treatment cessation. Next, the model was used to predict the expected amount of resistant enterobacteria excreted over an average piglet's lifetime (150 days) when varying drug exposure and treatment duration. For the clinically relevant dose of 15 mg/kg/day for 5 days, the total amount of resistant enterobacteria excreted was predicted to be reduced by 75% and 98% when reducing treatment duration to 3 and 1 day treatment, respectively. Alternatively, for a fixed 5-days treatment, the level of resistance excreted could be reduced by 18%, 33%, 57.5% and 97% if 3, 5, 10 and 30 times lower levels of colonic drug concentrations were achieved, respectively. This characterization on in vivo data of the dynamics of resistance to antibiotics in the colonic flora could provide new insights into the mechanism of dissemination of resistance and can be used to design strategies aiming to reduce it. PMID:25210849

  1. Effect of an acute oral ibuprofen intake on urinary aquaporin-2 excretion in healthy humans.

    PubMed

    Pedersen, R S; Bentzen, H; Bech, J N; Pedersen, E B

    2001-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the enzyme cyclooxygenase and thereby block the prostaglandin (PG) synthesis in the kidneys. In animals, PG interferes with the formation of aquaporin 2 in the distal renal tubules. The purpose was to measure the effect of ibuprofen on urinary excretion of aquaporin-2 (u-AQP2), urinary output, urinary osmolality (u-osm) and plasma concentration of vasopressin (AVP) in a dose-response study using placebo and ibuprofen 600mg and 1200mg. In 12 healthy subjects, urine was collected in 6 periods between 07.00 h and 13.00 h, and blood samples were drawn at 60-min intervals. The study medication was given 10 h and 1 h before the study. U-AQP2 and AVP were determined by radioimmunoassays. U-AQP2 decreased 33% in the placebo group and increased 47% in the ibuprofen groups. There was a highly significant difference between the placebo group, on the one hand, and the ibuprofen groups, on the other. There was a small but significant increase in AVP in the placebo group and the 600 mg ibuprofen group, but not in the 1200 mg ibuprofen group. Urinary output was at maximum after 2 h, with a 394%, 1020% and 714% increase for placebo, 600 mg ibuprofen and 1200 mg ibuprofen, respectively. U-osm decreased during the experiment in all three groups. Inhibition of renal prostaglandin synthesis by ibuprofen affects the distal part of the nephron by increasing u-AQP2. This increase was not related to changes in AVP, urinary output or urinary osmolality. We suggest that the increased excretion of AQP2 can be explained by an increase in the ratio of AQP2 that is shed into the urine because the endocytic retrieval of AQP2 from the apical membrane is impaired. This could not be revealed by changes in the osmoregulatory system by the low doses of ibuprofen used in the present study. PMID:11768323

  2. Total saponins from Discorea nipponica ameliorate urate excretion in hyperuricemic mice.

    PubMed

    Zhou, Qi; Yu, Dong-Hua; Zhang, Chong; Liu, Shu-Min; Lu, Fang

    2014-10-01

    Rhizoma Dioscoreae Nipponicae, from Discorea nipponica, is a widely used traditional Chinese herb. It is used to treat arthroncus, arthrodynia, and arthritis. Hyperuricemia is an important foundation of gouty arthritis. The current study was aimed at investigating whether the effects of total saponins from Rhizoma Dioscoreae Nipponicae on hyperuricemia were due to renal organic ion transporters in potassium oxonate-induced hyperuricemia mice. Hyperplasia of synovial cells prepared from Wistar rats was induced by IL-1β (1 × 10(4) µg/mL). MTT was used and to screen active components in the inhibition of hyperplasia by total saponins from Rhizoma Dioscoreae Nipponica, individual pure compounds, and different combinations of these compounds. Sixty Kun Ming mice were randomly divided into six groups: normal, model, allopurinol (40 mg/kg), and three total saponins groups receiving dose (600 mg/kg), middle (300 mg/kg), and low doses (60 mg/kg). Hyperuricemic mice were induced with potassium oxonate (300 mg/kg) intragastrically. The total saponins were given six days and the positive drug allopurinol was given one day before inducing hyperuricemia. The serum and urine levels of uric acid and creatinine and the fractional excretion of uric acid were measured in normal and hyperuricemic mice treated with Rhizoma Dioscoreae Nipponicae and allopurinol. The mRNA and protein levels of the mouse urate transporter 1, glucose transporter 9, organic anion transporter 1, and organic anion transporter 3 were analyzed by real-time-PCR and Western blotting methods, respectively. Total saponins from Rhizoma Dioscoreae Nipponicae could effectively reverse potassium oxonate-induced alterations in renal mouse urate transporter 1, glucose transporter 9, organic anion transporter 1, and organic anion transporter 3 mRNA and protein levels, resulting in enhancement of renal urate excretion in mice. These findings suggested that the total saponins from Rhizoma Dioscoreae

  3. Noninvasive Imaging of Administered Progenitor Cells

    SciTech Connect

    Steven R Bergmann, M.D., Ph.D.

    2012-12-03

    -99% pure population of leukocytes. Viability was assessed using Trypan blue histological analysis. We successfully isolated and labeled ~25-30 x 10{sup 7} CD34+ lymphocytes in cytokine mobilized progenitor cell apharesis harvests. Cells were also subjected to a stat gram stain to look for bacterial contamination, stat endotoxin LAL to look for endotoxin contamination, flow cytometry for evaluation of the purity of the cells and 14-day sterility culture. Colony forming assays confirm the capacity of these cells to proliferate and function ex-vivo with CFU-GM values of 26 colonies/ 1 x 10{sup 4} cells plated and 97% viability in cytokine augmented methylcellulose at 10-14 days in CO{sub 2} incubation. We developed a closed-processing system for the product labeling prior to infusion to maintain autologous cell integrity and sterility. Release criteria for the labeled product were documented for viability, cell count and differential, and measured radiolabel. We were successful in labeling the cells with up to 500 uCi/10{sup 8} cells, with viability of >98%. However, due to delays in getting the protocol approved by the FDA, the cells were not infused in humans in this location (although we did successfully use CD34+ cells in humans in a study in Australia). The approach developed should permit labeling of progenitor cells that can be administered to human subjects for tracking. The labeling approach should be useful for all progenitor cell types, although this would need to be verified since different cell lines may have differential radiosensitivity.

  4. Comparative metabolism studies of hexabromocyclododecane (HBCD) diastereomers in male rats following a single oral dose

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Male Sprague-Dawley rats were dosed orally with 3 mg/kg of one of three hexabromocyclododecane (HBCD) diastereomers. Each diastereomer was well absorbed (73-83%), and distributed preferentially to lipophilic tissues. Feces were the major route of excretion; cumulatively 42% of dose for alpha-HBCD,...

  5. Daytime cold exposure and salt intake based on nocturnal urinary sodium excretion: A cross-sectional analysis of the HEIJO-KYO study.

    PubMed

    Saeki, Keigo; Obayashi, Kenji; Tone, Nobuhiro; Kurumatani, Norio

    2015-12-01

    Increased cardiovascular incidence in winter is partly explained by higher blood pressure due to cold exposure. Although higher salt intake induced by cold exposure has been reported in mice, the association remains unclear in humans. To investigate the association between salt intake and cold exposure in winter, a cross-sectional study was conducted among 860 elderly subjects (mean ± standard deviation: 72.0 ± 7.1 years). We determined ambient temperature at every 10 min according to indoor temperature measured in the subjects' home, outdoor temperature, and self-administered diary logging time spent outdoors. Salt intake was estimated by nocturnal sodium excretion rate of overnight urine collection. A 1°C lower daytime ambient temperature was significantly associated with a higher urinary sodium excretion rate by 0.07 mmol/h in the subsequent night independent of age, sex, body weight, alcohol intake, calcium channel blocker use, diabetes, household income, estimated glomerular filtration rate, daytime physical activity (p=0.02). After further adjustment for outdoor temperature and day length, the lowest tertile groups of ambient daytime temperature (10.1 ± 2.3°C) showed the nocturnal urinary sodium excretion rate was higher by 14.2% (7.62 vs. 6.54 mmol/h) compared with the highest tertile group (19.3 ± 1.8°C). Higher sodium excretion rate was associated with higher nighttime ambulatory blood pressure (p<0.01) and its lower nocturnal dipping (p<0.01). Significant association between higher salt intake and daytime cold exposure partly explain the mechanism of higher blood pressure in winter, and suggest that a reduction of cold exposure might be effective to decrease salt intake. PMID:26476000

  6. A Grape Seed Procyanidin Extract Ameliorates Fructose-Induced Hypertriglyceridemia in Rats via Enhanced Fecal Bile Acid and Cholesterol Excretion and Inhibition of Hepatic Lipogenesis.

    PubMed

    Downing, Laura E; Heidker, Rebecca M; Caiozzi, Gianella C; Wong, Brian S; Rodriguez, Kelvin; Del Rey, Fernando; Ricketts, Marie-Louise

    2015-01-01

    The objective of this study was to determine whether a grape seed procyanidin extract (GSPE) exerts a triglyceride-lowering effect in a hyperlipidemic state using the fructose-fed rat model and to elucidate the underlying molecular mechanisms. Rats were fed either a starch control diet or a diet containing 65% fructose for 8 weeks to induce hypertriglyceridemia. During the 9th week of the study, rats were maintained on their respective diet and administered vehicle or GSPE via oral gavage for 7 days. Fructose increased serum triglyceride levels by 171% after 9 weeks, compared to control, while GSPE administration attenuated this effect, resulting in a 41% decrease. GSPE inhibited hepatic lipogenesis via down-regulation of sterol regulatory element binding protein 1c and stearoyl-CoA desaturase 1 in the fructose-fed animals. GSPE increased fecal bile acid and total lipid excretion, decreased serum bile acid levels and increased the expression of genes involved in cholesterol synthesis. However, bile acid biosynthetic gene expression was not increased in the presence of GSPE and fructose. Serum cholesterol levels remained constant, while hepatic cholesterol levels decreased. GSPE did not modulate expression of genes responsible for esterification or biliary export of the newly synthesized cholesterol, but did increase fecal cholesterol excretion, suggesting that in the presence of GSPE and fructose, the liver may secrete more free cholesterol into the plasma which may then be shunted to the proximal small intestine for direct basolateral to apical secretion and subsequent fecal excretion. Our results demonstrate that GSPE effectively lowers serum triglyceride levels in fructose-fed rats after one week administration. This study provides novel insight into the mechanistic actions of GSPE in treating hypertriglyceridemia and demonstrates that it targets hepatic de novo lipogenesis, bile acid homeostasis and non-biliary cholesterol excretion as important mechanisms for

  7. A Grape Seed Procyanidin Extract Ameliorates Fructose-Induced Hypertriglyceridemia in Rats via Enhanced Fecal Bile Acid and Cholesterol Excretion and Inhibition of Hepatic Lipogenesis

    PubMed Central

    Wong, Brian S.; Rodriguez, Kelvin; Del Rey, Fernando; Ricketts, Marie-Louise

    2015-01-01

    The objective of this study was to determine whether a grape seed procyanidin extract (GSPE) exerts a triglyceride-lowering effect in a hyperlipidemic state using the fructose-fed rat model and to elucidate the underlying molecular mechanisms. Rats were fed either a starch control diet or a diet containing 65% fructose for 8 weeks to induce hypertriglyceridemia. During the 9th week of the study, rats were maintained on their respective diet and administered vehicle or GSPE via oral gavage for 7 days. Fructose increased serum triglyceride levels by 171% after 9 weeks, compared to control, while GSPE administration attenuated this effect, resulting in a 41% decrease. GSPE inhibited hepatic lipogenesis via down-regulation of sterol regulatory element binding protein 1c and stearoyl-CoA desaturase 1 in the fructose-fed animals. GSPE increased fecal bile acid and total lipid excretion, decreased serum bile acid levels and increased the expression of genes involved in cholesterol synthesis. However, bile acid biosynthetic gene expression was not increased in the presence of GSPE and fructose. Serum cholesterol levels remained constant, while hepatic cholesterol levels decreased. GSPE did not modulate expression of genes responsible for esterification or biliary export of the newly synthesized cholesterol, but did increase fecal cholesterol excretion, suggesting that in the presence of GSPE and fructose, the liver may secrete more free cholesterol into the plasma which may then be shunted to the proximal small intestine for direct basolateral to apical secretion and subsequent fecal excretion. Our results demonstrate that GSPE effectively lowers serum triglyceride levels in fructose-fed rats after one week administration. This study provides novel insight into the mechanistic actions of GSPE in treating hypertriglyceridemia and demonstrates that it targets hepatic de novo lipogenesis, bile acid homeostasis and non-biliary cholesterol excretion as important mechanisms for

  8. Daily intake and urinary excretion of genistein and daidzein by infants fed soy- or dairy-based infant formulas.

    PubMed

    Irvine, C H; Shand, N; Fitzpatrick, M G; Alexander, S L

    1998-12-01

    Our aims were to measure isoflavone intake from soy- and dairy-based infant formulas and breast milk and to assess the ability of infants to digest and absorb soy isoflavones by measuring daily urinary excretion rates. We recruited 29 infants: 4 received soy-based formula and 25 received dairy-based formula. We collected pooled urine samples from 3-5 disposable diapers worn during a 24-h period and developed and validated methods for extracting isoflavones from the diapers. Infants were studied every 1 or 2 wk, starting at 2-6 wk of age and continuing until 16 wk. Only soy-based formulas contained isoflavones in concentrations detectable by HPLC (limits: 0.05 mg/L for liquids and 0.1 mg/kg for solids). Soy-based formulas provided a mean (+/-SEM) daily dose of isoflavones (genistein plus daidzein) of 3.2 +/- 0.2 mg/kg body wt, which remained fairly constant (CV: 12%) regardless of age < or = 16 wk. Isoflavones were measurable in all samples from soy-fed infants, but not in urine from dairy-fed infants. Daily isoflavone excretion rates varied little among infants [range of mean individual values (mg x kg(-1) d(-1)): daidzein, 0.37 +/- 0.03 to 0.58 +/- 0.06; genistein, 0.15 +/- 0.03 to 0.32 +/- 0.04] and did not change with age < or = 16 wk. The mean percentage of the daily intake recovered in the urine of soy-fed infants was 38 +/- 4% for daidzein and 13 +/- 3% for genistein, and remained constant with age. These values are similar to those for adults and indicate that young infants are able to digest, absorb, and excrete genistein and daidzein from soy-based formulas as efficiently as do adults consuming soy products. PMID:9848517

  9. Pharmacokinetics and tolerance of DU-6859a, a new fluoroquinolone, after single and multiple oral doses in healthy volunteers.

    PubMed Central

    Nakashima, M; Uematsu, T; Kosuge, K; Umemura, K; Hakusui, H; Tanaka, M

    1995-01-01

    The pharmacokinetics and tolerance of DU-6859a, 7-[(7S)-7-amino-5-azaspiro[2,4]heptan-5-yl]-8-chloro-6-fluor o-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid sesquihydrate, were investigated in healthy male Japanese volunteers after single (25, 50, 100, and 200 mg) and multiple (100 mg three times a day for 6 days plus once a day on the 7th day and 50 mg every 12 h for 13 doses) oral doses. DU-6859a was well tolerated at all doses, and all 36 subjects completed the study; mild transient soft stool in five volunteers and mild transient diarrhea in one volunteer on the multiple-dose (100 mg three times a day) study were the only side effects reported. No drug crystals were observed in the urine after the single 200-mg dose and the 100-mg three times a day regimen. DU-6859a was rapidly absorbed in the fasted state. The mean maximum concentration in serum (Cmax) ranged from 0.29 to 1.86 micrograms/ml for the 25- to 200-mg dose, and the mean time to reach Cmax ranged from 1.0 to 1.3 h. The terminal half-life ranged from 4.4 to 5.0 h. The area under the curve increased dose dependently. The serum protein binding of the drug was approximately 50%. The apparent volume of distribution clearly exceeded 1 liter/kg, suggesting good tissue penetration. Within 48 h, the cumulative urinary recovery of unchanged drug amounted to 69 to 74% of the dose administered, while fecal excretion up to 48 h after the 200-mg dose accounted for ca. 3% of the dose. Food intake did not affect the rate and extend of absorption of DU-6859a to a clinically significant extent. During multiple oral dosing, the accumulation of the drug in serum was close to the theoretically predicted values, which indicated that there was virtually no drug accumulation. PMID:7695301

  10. Variability of urinary salt excretion estimated by spot urine in treated hypertensive patients.

    PubMed

    Arakawa, Kimika; Sakaki, Minako; Sakata, Satoko; Oniki, Hideyuki; Tominaga, Mitsuhiro; Tsuchihashi, Takuya

    2015-01-01

    Among the several methods used to assess salt intake, estimating 24 h urinary salt excretion by spot urine seems appropriate for clinical practice. In this study, we investigated variability in urinary salt excretion using spot urine in hypertensive outpatients. Participants included 200 hypertensive patients who underwent spot urinary salt excretion at least three times during the observation period. Mean urinary salt excretion and the coefficient of the variation were 8.62 ± 1.96 g/day and 19.0 ± 10.2%, respectively. In the analysis of participants who underwent assessment of urinary salt excretion at least eight times (n = 54), a significant reduction in mean urinary salt excretion was found at the 5th measurement. On the contrary, the coefficient of the variation of urinary salt excretion continued to increase until the 5th measurement, and became stable thereafter. Mean urinary salt excretion was positively correlated with mean clinic diastolic blood pressure (r = 0.27, p < 0.05). Clinic diastolic blood pressure in the high urinary salt excretion group (≥ 10 g/day) was significantly higher than that of the low group (76.2 ± 7.5 vs 73.4 ± 8.3 mmHg, p < 0.05). Mean urinary salt excretion in summer was significantly lower than that of the other seasons (7.75 ± 1.94 vs 9.09 ± 2.68 (spring), 8.72 ± 2.12 (autumn), 8.92 ± 2.17 (winter) g/day, p < 0.01). In conclusion, repeated measurements of urinary salt excretion using spot urine are required to assess daily salt intake of hypertensive patients. PMID:26395949

  11. Excretion of artifactual endogenous digitalis-like factors

    SciTech Connect

    Kelly, R.A.

    1986-07-01

    Radioimmunoassays have been used to detect digoxin-like immunoreactive factors (DLF) in the plasma and urine of hypertensive patients and rats with deoxycorticosterone acetate (DOCA)-salt hypertension. DLF, partially purified from DOCA-HS urine by antidigoxin antibody immunoaffinity chromatography, was found to have a molecular weight <2000. When DOCA-HS rats were switched to the low-sodium chow, DLF excretion dropped precipitously. No measurable DLF was detected in the plasma of rats eating either chow. However, >95% of the urinary DLF could be attributed to a contaminant in the standard laboratory chow. These data document the importance of excluding nonspecific compounds and exogenous sources of DLF when sensitive radioligand and biologic assays are used to detect endogenous inhibitors of the sodium pump.

  12. Impact of Aging on Urinary Excretion of Iron and Zinc

    PubMed Central

    Pfrimer, Karina; Micheletto, Rutinéia Fátima; Marchini, Julio Sergio; Padovan, Gilberto João; Moriguti, Julio Cesar; Ferriolli, Eduardo

    2014-01-01

    PROJECT Data about the influence of aging on urinary excretion of iron and zinc are scarce. The objective of the present study was to compare the concentration of zinc and iron in the urine of healthy elderly subjects and younger adults. PROCEDURE Seven healthy elderly subjects and seven younger adults were selected and submitted to biochemical, clinical, and nutritional tests. After a fasting period, 12-hour urine was collected for the determination of iron and zinc concentrations by graphite furnace atomic absorption spectrophotometry. RESULTS Urinary zinc and iron concentrations of the elderly subjects were not significantly different from that of younger adults. However, the total zinc and iron urinary clearance in 24 hours for the elderly was significantly higher compared with that of younger adults. CONCLUSION There is an increase in urinary iron and zinc clearance with aging. The values reported in this manuscript may be used as references in future studies. PMID:24932105

  13. Urinary 6 beta-hydroxycortisol excretion in rheumatoid arthritis.

    PubMed

    Beyeler, C; Frey, B M; Bird, H A

    1997-01-01

    The objective was to analyse whether the activity of the cytochrome P450 isoenzyme CYP3A4 is altered by disease activity of rheumatoid arthritis (RA). Urinary 6 beta-hydroxycortisol excretion, expressed as a fraction of the urinary creatinine output, was measured in 21 patients with RA treated with three different disease-modifying anti-rheumatic drugs (DMARDs) over 24 weeks. There were no correlations between urinary 6 beta-hydroxycortisol/creatinine (6 beta-OHC/Creat) ratio and measurements of disease activity such as plasma viscosity, Ritchie articular index and early morning stiffness. In addition, the three DMARDs sulphasalazine, sodium aurothiomalate and D-penicillamine, smoking and the intake of various CYP3A4 substrates had no consistent detectable effect on the 6 beta-OHC/Creat ratio. There is no evidence that the dosage of drugs metabolized by the CYP3A4 isoenzyme needs to be adjusted for disease activity in RA. PMID:9117175

  14. Disposition and metabolism of cabotegravir: a comparison of biotransformation and excretion between different species and routes of administration in humans.

    PubMed

    Bowers, Gary David; Culp, Amanda; Reese, Melinda J; Tabolt, Glenn; Moss, Lee; Piscitelli, Stephen; Huynh, Phuong; Wagner, David; Ford, Susan L; Gould, Elizabeth P; Pan, Rennan; Lou, Yu; Margolis, David A; Spreen, William R

    2016-01-01

    1.  Cabotegravir [(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide] is an HIV-1 integrase inhibitor under development as a tablet for both oral lead-in therapy and long-acting (LA) injectable for intramuscular dosing. 2. Metabolism, pharmacokinetics and excretion were investigated in healthy human subjects who received either a single oral dose (28.2 mg) of [(14)C]cabotegravir in a mass balance study, or LA formulations of unlabeled cabotegravir (200-800 mg), intramuscularly or subcutaneously, in a separate study. Metabolism, distribution and excretion of [(14)C]cabotegravir were also investigated in mice, rats and monkeys. 3. Recovery of radioactivity in humans represented a mean total of 85.3% of the dose, including 26.8% in the urine. The mean apparent terminal phase half-life was similar for both cabotegravir and radioactivity, 39 h compared to 41 h. 4. Following oral, intramuscular and subcutaneous administration, cabotegravir was the major component in plasma and the glucuronic acid conjugate (M1) represented the predominant component in urine. Cabotegravir was present in bile along with its major metabolite (M1). 5. The primary metabolite of [(14)C]cabotegravir in mouse, rat and monkey was the same as that in human. In vitro phenotyping experiments demonstrated that cabotegravir was metabolized by UDP-glucuronosyltransferase (UGT) 1A1 and UGT1A9. PMID:26134155

  15. Protection of Eurasian badgers (Meles meles) from tuberculosis after intra-muscular vaccination with different doses of BCG.

    PubMed

    Lesellier, Sandrine; Palmer, Si; Gowtage-Sequiera, Sonya; Ashford, Roland; Dalley, Deanna; Davé, Dipesh; Weyer, Ute; Salguero, F Javier; Nunez, Alejandro; Crawshaw, Timothy; Corner, Leigh A L; Hewinson, R Glyn; Chambers, Mark A

    2011-05-12

    Mycobacterium bovis infection is widespread in Eurasian badger (Meles meles) populations in Great Britain and the Republic of Ireland where they act as a wildlife reservoir of infection for cattle. Removal of infected badgers can significantly reduce the incidence of bovine tube