bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in salicylate serum concentration and metabolism during chronic dosing in normal volunteers
Authors: Day Richard O. , Furst Daniel E. , Dromgoole Sydney H. , Paulus Harold E.
Published: October 2006

Steady‐state serum salicylic acid (SA) concentrations and the formation rates of salicyluric acid (SU), salicylphenolic glucuronide (SPG), salicylacyl glucuronide (SAG), and gentisic acid (GA), and the excretion rate of unchanged SA were determined in three normal subjects following the administration of a single oral dose of acetylsalicylic acid (ASA) 37 mg kg−1 and during multiple dosing with ASA 56 mg kg−1 day.−1 Steady‐state SA concentrations fell 23 per cent during the 4‐week study period (mean ± SD: 239 ± 35 to 183 ± 23 μg ml−1;p < 0.05). Absorption of drug did not decrease during this time. Significant increases in the Vmax for SU and SPG formation occurred between baseline and during multiple dosing. Mean VmaxSU increased from 0.93 to 1.68 mg kg−1 h−1 (p < 0.05) and mean Vmax SPG increased from 009 to 019 mg kg−1h−1 (p<005). First‐order rate constants for the formation of SAG and GA and for the excretion of unchanged SA did not change significantly between baseline and multiple dosing. The mechanism for the decline in CpssSA with time during high‐dose SA therapy is most likely due to the induction of the formation rates of the major metabolites of SA, namely SU and SPG.
Pharmacokinetics of caffeine in breast milk and plasma after single oral administration of caffeine to lactating mothers
Authors: Stavchansky S. , Delgado M. , Joshi A. , Combs A. , Sagraves R.
Published: October 2006

Six healthy lactating women ranging in age from 28 to 35 years were selected to participate in the study. The women had been nursing their infants from 3½ weeks up to 17 weeks. On the morning of the study each participant received 100 mg dose of caffeine. The oral dose of caffeine was taken with a glass of water on an empty stomach. Blood samples were collected from zero time to 24 h after caffeine administration. Each subject aseptically collected breast milk from the right and left breasts by manual expression or using a mechanical breast pump, from zero time to 24 h after caffeine administration. Caffeine in plasma and breast milk was determined by gas liquid chromatography using nitrogen phosphorous detection.

Caffeine was rapidly absorbed producing plasma time to peaks ranging from 0.50 to 1.00h, with values for peak concentrations between 360 and 6.15 μgml−1 in plasma. In breast milk, time‐to peak ranged from 0.75 to 2.00 h and concentration values between 1.98 and 4.30 μgml−1 No significant differences were found between attainment of the time of the peak in plasma and breast milk, p>0.05. In addition, peak concentration for the right and left breast were not statistically different, p>0.05. However, significant differences, p>0.05, between plasma and both breasts in regards to the peak concentrations were found. The overall breast milk/ plasma ratio obtained from the respective area under the curves were 0.815 ± 0.0521 and 0.809 ± 0.202 for the right and left breast, respectively, and no statistical differences were observed between the right and left breasts, p>0.05.

In summary, caffeine is rapidly transferred to breast milk. Multiple dose studies are needed to provide more information about caffeine concentration in breast milk of women who receive multiple doses of caffeine or who chronically consume caffeine.
In vitro protein binding interaction studies involving cefixime
Authors: Bialer Meir , Wu Wen Hui , Faulkner Robert D. , Michael Silber B. , Yacobi Avraham
Published: October 2006

Cefixime is a new oral cephalosporin currently undergoing clinical trials. Selected agents with the likelihood for coadministration with cefixime in man were examined for their influence on the in vitro binding of cefixime in pooled serum from dog, monkey, and man. Results from these experiments showed no significant change in cerfixime binding in any animal species studied or in man by acetaminophen, heparin, phenytoin, diazepam, ibuprofen or furosemide at their maximum reported therapeutic concentrations. In contrast, both salicylic acid and probenecid resulted in concentration‐dependent increases in the free fraction of cefixime (up to 2.5‐fold). These findings demonstrate the usefulness of in vitro protein binding screening procedures for studying potential drug interactions that are mediated, at least in part, by changes in the protein binding of a drug.
Elevation of gastric pH with ranitidine does not affect the release characteristics of sustained release ibuprofen tablets
Authors: Berardi Rosemary R. , Dressman Jennifer B. , Elta Grace H. , Szpunar Gregory J.
Published: October 2006

The effect of elevating gastric pH on the release characteristics of a single unit sustained release (SR) ibuprofen tablet (MOTRIN‐SR®, Upjohn) was evaluated in 12 young, healthy men. Using a randomized crossover‐type design, each subject received three treatments – ibuprofen SR 800 mg, ranitidine 300 mg followed by ibuprofen SR 800 mg, and conventional ibuprofen tablets (2 × 400 mg). Gastric pH, which was monitored radiotelemetrically, was maintained above pH 6 for at least 4 h after pretreatment with ranitidine. In absence of ranitidine, the pH remained mostly below pH 3. Serum levels of ibuprofen were measured for 24 h and urine was collected for 48 h after each treatment. Similarity of the serum levels after the two treatments with ibuprofen SR 800 mg indicated that the release of ibuprofen was unaffected by elevation in gastric pH. Comparison of profiles with the immediate release dosage form indicated that dose dumping did not occur in any subject.
Pharmacokinetics of cefazolin administered as a new drug delivery system in healthy volunteers
Authors: Lanao J. M. , Vicente M. T. , Dominguez‐Gil A.
Published: October 2006

A study was made of the pharmacokinetic behaviour in plasma and urine of cefazolin in seven healthy volunteers following parenteral administration of sodium cefazolin (1250 mg) and a sustained release formulation containing sodium cefazolin: cefazolin‐dibenzylamine (1:4) at a total dose of 1250 mg, both formulations being administered over 1 week by the i.m. route. Cefazolin concentrations in plasma and urine were determined by a HPLC technique. Kinetic analysis of the experimental results was performed using an open single‐compartment kinetic model and a sustained release model for the drug administered as standard formulation and the sustained release formulation, respectively. The results obtained point to significant variations in the pharmacokinetic profile of the drug when administered in the DDS.

The time of cefazolin at levels greater than 1 μgml was 16.03 ± 2.51 and 47.76 ± 14.18h after administration of the standard formulation and the DDS, respectively. The urinary excretion rate curves also show the existence of sustained drug levels in the urine following administration of the DDS. The renal clearance of the drug did not show statistically significant differences between the two formulations administered. The process of release of cefazolin from the cefazolin‐dibenzylamine complex proved to be a first order kinetic process. The release constant of the antibiotic was calculated according to three different methods the Wagner‐Nelson method; the statistical moments method; and the fitting of the plasma levels curves to a compartmental model considering release and absorption. The values obtained for this constant ranges from 0.026 ± 0.02 h calculated with the method of statistical moments to 0.094 ± 0.03 h as calculated by the equation derived for the plasma fitting of cefazolin administered as DDS.
Choice of optimum pharmacokinetic model of orally administered paracetamol
Authors: Pedraz J. L. , Calvo M. B. , Lanao J. M. , Dominguez‐Gil A.
Published: October 2006

The present work studies the characterization of the pharmacokinetic profile of paracetamol following oral administration of DUOROL® tablets containing 500 mg of the active compound. Analysis is made of the influence of statistical weighting on the selection of the pharmacokinetic model chosen. In the model proposed, the uptake of the drug into the systemic circulation is described by two first‐order sequential kinetic processes. The values of the first order rate constants that define the absorption process have values of 4.79 and 9.73h−1. Validation of the absorption model proposed was performed by applying the Wagner‐Nelson method, according to which values of 4.63 and 10.95 h−1 were obtained for each of the constants defining the uptake of the drug into the systemic circulation.
Noncompartmental area under the curve determinations for drugs that cycle in the bile
Authors: Colburn Wayne A. , Lucek Rudolph W.
Published: October 2006

Drugs that are involved in the enterohepatic circulation (EHC) generally exhibit complex disposition profiles and are difficult to describe by classical methods. A noncompartmental method for calculating the area under the curve from time zero to time infinity (AUC) for substances that are involved the EHC is developed and tested. Previous methods have been based on specific compartmental models and/or have been limited to a single enterohepatic cycle. The current method uses the following equations:
equation image

For an oral dose where kaR is the apparent first‐order absorption rate constant and βR is the rate constant that describes the decline in blood concentrations of drug at 24‐h intervals, i.e., 12, 36, and 60 or 24, 48, and 72 h, etc. AUC0–24 can be calculated by trapezoidal summation. The precision of this method is dependent on the number of observations during the 0‐24 h sampling period as well as the accuracy of KaR and βR. For drugs that are subject to a distinct distribution phase(s), error can be introduced into the AUC0‐00 value if pseudo‐equilibrium has not been achieved during the first 24‐hour interval. Although the method depends on a linearization process, it is truly concompartmental (‘model‐independent’) in nature.
Pharmacokinetics of 14C‐etretinate in healthy volunteers and two patients with biliary t‐tube drainage
Authors: Lucek Rudolph W. , Bugge Christopher J. L. , Crews Ted , Vane Floie M. , Cunningham W. , Colburn Wayne A. , Dickerson Janet , Carter Dean E.
Published: October 2006

The pharmacokinetic profile of 14C‐etretinate, a retinoid that is effective in the treatment of psoriasis, was studied in six healthy male volunteers and two biliary T‐tube patients. Following a 100 mg oral dose of 14C‐etretinate (20 microcurie), etretinate and its major blood metabolites (etretin, isoetretin) were measured by HPLC and total carbon‐14 was measured in blood, bile, urine, and feces by liquid scintillation counting. Etretinate was extensively metabolized in healthy volunteers and in T‐tube patients. During the absorption phase, 75 per cent of the total radioactivity in the blood could be accounted for as etretinate, etretin, and isoetretin whereas these compounds accounted for only approximately 12 per cent of the blood radioactivity in T‐tube patients over the same time period. The blood concentrations of etretinate, etretin, and isoetretin appeared to be substantially reduced in T‐tube patients compared to those in healthy volunteers. A higher proportion of the total drug was excreted in the feces and bile of the T‐tube patients (84 per cent) than in the feces of healthy volunteers (62 per cent). The major factor responsible for the observed decrease in etretinate blood concentrations following biliary cannulation appears to be the reduced absorption of etretinate due to the elimination of solubilizing bile salts in the duodenum. Carbon‐14 related material was detected in urine and feces for as long as 3 weeks in healthy subjects supporting the previous observation that a long terminal elimination half‐life exists for etretinate, even following a single dose of the compound.
Comparative human study of ibuprofen enantiomer plasma concentrations produced by two commercially available ibuprofen tablets
Authors: Cox S. R. , Brown M. A. , Squires D. J. , Knuth D. W. , Murrill E. A. , Lednicer D.
Published: October 2006

Twelve healthy male subjects participated in a two‐way Latin square crossover study in which the treatments were a single 400 mg generic ibuprofen tablet (Tablet A) or a single 400 mg MOTRIN® Tablet (Tablet B). Blood samples were drawn at various times through 12 h after dosing and plasma samples were assayed for ibuprofen enantiomers with a stereospecific capillary gas chromatographic procedure. Concentration‐time data for both enantiomers were in agreement and indicated that drug was absorbed much more quickly from Tablet B than from the Tablet A; enantiomer Tmax values were less than 1.3 h from Tablet B but longer than 4 h from the Tablet A (p<0.001). Also, maximum enantiomer plasma concentrations from the Tablet B were about 50 per cent of the peak concentrations observed from Tablet A (p<0.001). The total extent of drug absorption appeared to be the same in both products. These data clearly indicate that the two tablets are not bioequivalent with respect to either ibuprofen enantiomer.
Pharmacokinetics of nitroglycerin and metabolites in humans following oral dosing
Authors: K. Yu Dale , Giesing Dennis H. , Williams Roger L. , Benet Leslie Z. , Lin Emil T.
Published: October 2006

Single dose oral nitroglycerin (GTN) was administered to six healthy subjects as 6.5, 9.0, and 13.0 mg aqueous solutions in sequential study phases to characterize the oral pharmacokinetics of GTN and the dinitrate metabolites. Blood samples were collected periodically up to 10 h. Plasma concentrations of GTN were measurable in some subjects up to 1/2 and 1 h, respectively, after the 9.0 and 13.0 mg dose. The mean GTN Cmax values of the three solution doses were 0.28, 0.78, and 0.42 ng ml−1 in ascending dosage. The erratic nature of GTN plasma profiles prevented meaningful pharmacokinetic analysis, although tmax was consistently 5 min. In all three treatments, both GTN metabolites (1,2‐and 1,3‐glyceryldinitrates, GDNs) peaked at about 20 min, followed by a distributive phase and a log‐linear decline in concentrations. Terminal half‐lives for both GDNs were approximately 50 min in all three doses. The plasma concentrations of the metabolites were higher than nitroglycerin with 1,2‐GDN exhibiting the highest overall profile.
Standardization of pelvic lymphadenectomy performed at radical cystectomy
Authors: Koppie Theresa M. , Vickers Andrew J. , Vora Kinjal , Dalbagni Guido , Bochner Bernard H.
Published: October 2006

BACKGROUND.

The number of lymph nodes (LNs) removed during radical cystectomy (RC) for transitional cell carcinoma (TCC) of the bladder affects overall and disease‐specific survival, but no consensus exists regarding the minimum number of LNs that should be removed. The goal of the current study was to determine if a threshold number of nodes exists, above which taking additional LNs has no clinical benefit.

METHODS.

A total of 1121 patients were identified who underwent RC for clinically localized TCC of the bladder between January 1990 and April 2004. To determine the relation of LNs removal and overall survival, a Cox proportional hazards model was used with pathologic stage, age, and comorbidity as covariates. A dose‐response curve, adjusted for covariates, was modeled to assess the impact of an increasing number of LNs removed on overall survival.

RESULTS.

A median of 9 LNs were removed (range, 0–53 LNs). In multivariable analysis, all covariates (number of LNs removed, age, stage of disease, and comorbidity) were found to be predictive of survival. The dose‐response curve for number of LNs versus survival revealed that, when adjusted for covariates, the probability of survival did not plateau but instead continued to rise as the number of LNs removed increased.

CONCLUSIONS.

No evidence was found that a minimum number of LNs is sufficient for optimizing bladder cancer outcomes when a limited or extended pelvic LN dissection is performed during RC. Instead, the probability of survival continues to rise as the number of LNs removed increases. This study supports a more extended LN dissection at the time of RC, and highlights the challenges of interpreting retrospective LN dissection data. Cancer 2006. © 2006 American Cancer Society.
Survival of men with clinically localized prostate cancer treated with prostatectomy, brachytherapy, or no definitive treatment
Authors: Tward Jonathan D. , Lee Christopher M. , Pappas Lisa M. , Szabo Aniko , Gaffney David K. , Shrieve Dennis C.
Published: October 2006

BACKGROUND.

The optimal treatment for men with early stage prostate cancer remains undefined. Survival of such patients after surgery, brachytherapy, or no definitive therapy was investigated specifically to determine the impact of age at diagnosis.

METHODS.

In all, 60,290 men diagnosed with organ‐confined, low and moderate grade prostate cancer between 1988 and 2002 were retrospectively identified from centers participating in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. Prostate cancer‐specific mortality (PCSM) and any‐cause mortality (ACM) were determined. Outcomes for patients treated by brachytherapy, surgery, or receiving no definitive treatment were compared using the Wilcoxon test, stratified by T‐stage and grade, and using multivariate analysis.

RESULTS.

The median follow‐up time was 46 months (range, 0–189 months). For men under age 60 at diagnosis, PCSM at 10 years was 1.3%, 0.5%, and 3.7% for surgery, brachytherapy, and no definitive therapy, respectively. For men age 60 and older the PCSM was 3.8%, 5.3%, and 8.4%, respectively. On univariate and multivariate analysis, surgery and brachytherapy resulted in statistically equivalent PCSM and ACM, and both had a significantly lower PCSM and ACM versus no definitive therapy.

CONCLUSIONS.

A better survival was observed in men treated with a definitive therapy. The magnitude of the benefit on PCSM or ACM was similar for both definitive therapies irrespective of age. Cancer 2006. © 2006 American Cancer Society.
Mice expressing high levels of soluble CD14 retain LPS in the circulation and are resistant to LPS‐induced lethality
Authors: Jacque Berri , Stephan Kristin , Smirnova Irina , Kim Bobae , Gilling Damian , Poltorak Alexander
Published: October 2006

Despite significant progress in understanding the origin of soluble CD14 (sCD14), its physiological function remains largely unknown. Recent research has produced contradictory observations suggesting that sCD14 may have either beneficial or detrimental properties in protection against LPS‐induced endotoxin shock. To resolve this controversy and to establish a mouse model suitable for elucidation of the functions of human CD14 (hCD14) in vivo, we generated several lines of transgenic mice bearing different copy numbers of the hCd14 transgene on a murine Cd14–/– background. The hCD14 was entirely capable of complementing loss of mouse CD14 to mediate cellular responses to LPS. Serum levels of sCD14 in a founder with multiple copies of the transgene were several times higher than in transgenic animals with a single copy of Cd14. Furthermore, mice with high levels of hCD14 were hypo‐responsive to LPS and survived a lethal dose of LPS. Further inquiry into the mechanism of the hypo‐response to LPS revealed that protection is associated with the higher amounts of circulating LPS. Most of this circulating LPS can be immunoprecipitated with anti‐CD14 antibodies. These results suggest that sCD14 blocks circulating LPS by limiting the amount of monocyte‐bound LPS and thus reduces inflammatory responses.
A critical role for ICOS co‐stimulation in immune containment of pulmonary influenza virus infection
Authors: Humphreys Ian R. , Edwards Lorna , Snelgrove Robert J. , Rae Aaron J. , Coyle Anthony J. , Hussell Tracy
Published: October 2006

Lung pathology observed during influenza infection is due to direct damage resulting from viral replication and bystander damage caused by overly exuberant antiviral immune mechanisms. In the absence of universally effective vaccines and antiviral therapies, knowledge of the cellular components required for immune containment of influenza is essential. ICOS is a late co‐stimulatory molecule expressed by T cells 12–24 h after activation. We show for the first time that inhibition of ICOS with a monoclonal antibody reduces pulmonary T cell inflammation and associated cytokine expression. Surprisingly however, this reduction in T cells was not accompanied by an alleviation of weight loss and illness. Furthermore, lung viral titres were elevated following anti‐ICOS treatment, suggesting that the beneficial outcome of reducing T cell pathology was masked by enhanced virus‐induced damage and innate inflammation. This study demonstrates the delicate balance that exists between pathogen burden and pulmonary T cell inflammation during influenza infection and highlights the critical role of ICOS in this response.
Neutralization of IL‐17 by active vaccination inhibits IL‐23‐dependent autoimmune myocarditis
Authors: Sonderegger Ivo , Röhn Till A. , Kurrer Michael O. , Iezzi Giandomenica , Zou Yu , Kastelein Robert A. , Bachmann Martin F. , Kopf Manfred
Published: October 2006

The most common reason for heart failure in young adults is dilated cardiomyopathy often resulting from myocarditis. Clinical studies and animal models provide evidence that an autoimmune response against heart myosin is the underlying reason for the disease. IL‐12 has been suggested to play a key role in development of experimental autoimmune myocarditis (EAM), as IL‐12p40 and IL‐12Rβ1 knockouts are protected from disease. In this study, we have compared IL‐12p40–/– mice, IL‐12p35–/– mice and mice treated with a neutralizing IL‐23 antibody in EAM and found that in fact IL‐23, not IL‐12, is responsible for inflammatory heart disease. However, these cytokines appear to have redundant activity for priming and expansion of autoreactive CD4 T cells, as specific T cell proliferation was only defective in the absence of both cytokines. IL‐23 has been suggested to promote a pathogenic IL‐17‐producing T cell population. We targeted IL‐17 by capitalizing on an active vaccination approach that effectively breaks B cell tolerance. Neutralization of IL‐17 reduced myocarditis and heart autoantibody responses, suggesting that IL‐17 is the critical effector cytokine responsible for EAM. Thus, targeting of IL‐23 and IL‐17 by passive and active vaccination strategies holds promise as a therapeutic approach to treat patients at risk for development of dilated cardiomyopathy.

See accompanying commentary: http://dx.doi.org/10.1002/eji.200636760
Synthesis of Methyl Metallocenecarboxylates [{η4‐Ph4–n(SiMe3)nC4}Co{η5‐MeOC(O)C5H4}] (n = 1, 2) and Their Desilylation Reactions: Structural Studies and Conversion to Metallocenecarboxylic Acids and Their Alcohol Derivatives
Authors: Gupta Hanuman P. , Kumar M. Senthil , Upreti Shailesh , Elias Anil J.
Published: October 2006

The reaction of (2‐phenylethynyl)trimethylsilane (Me3SiC≡CPh) with [{η5‐MeOC(O)C5H4}Co(PPh3)2] generated in situ results in the exclusive formation of two isomers of methyl metallocenecarboxylates, namely [{trans‐η4‐Ph2(Me3Si)2C4}Co{η5‐MeOC(O)C5H4}] (1) and [{cis‐η4‐Ph2(Me3Si)2C4}Co{η5‐MeOC(O)C5H4}] (2). The reaction of [{η5‐MeOC(O)C5H4}Co(PPh3)(Me3SiC≡CPh)] with PhC≡CPh yields the methyl metallocenecarboxylate [{η4‐Ph3(Me3Si)C4}Co{η5‐MeOC(O)C5H4}] (3) along with [{η4‐Ph4C4}Co{η5‐MeOC(O)C5H4}] (4). The reactions of 1, 2 and 3 with Bu4NF in dmso results in the desilylated complexes [(trans‐η4‐Ph2H2C4)Co{η5‐MeOC(O)C5H4}] (5), [(cis‐η4‐Ph2H2C4)Co{η5‐MeOC(O)C5H4}] (6) and [(η4‐Ph3HC4)Co{η5‐MeOC(O)C5H4}] (7), respectively. Compounds 5, 6 and 7 yield the carboxylic acids [(trans‐η4‐Ph2H2C4)Co{η5‐HOC(O)C5H4}] (8), [(cis‐η4‐Ph2H2C4)Co{η5‐HOC(O)C5H4}] (9) and [(η4‐Ph3HC4)Co{η5‐HOC(O)C5H4}] (10) upon treatment with KOtBu in dmso. Reduction of 5 and 7 with LiAlH4 in thf gives the alcohol complexes [(trans‐η4‐Ph2H2C4)Co(η5‐HOCH2C5H4)] (11) and [(η4‐Ph3HC4)Co(η5‐HOCH2C5H4)] (12) in good yields. Compounds 1–7 and 11 were characterized structurally. These structural studies show interesting variations in the orientations of the cyclobutadiene‐bound phenyl groups when the silyl groups are systematically removed from the cyclobutadiene moiety. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
Material Aspects of the Design and Operation of Direct Borohydride Fuel Cells
Authors: Cheng H. , Scott K. , Lovell K.
Published: October 2006

The direct borohydride fuel cell (DBFC) has attracted increasing interest as a potential high power source for mobile and portable applications. Engineering design plays an important role in the development of the DBFC. This paper reports data for the selection of anode, cathode, and membrane materials for the DBFC. The best DBFC performance is achieved with a Au anode, a Pt cathode, and a 3541P ion exchange membrane. The use of non‐precious catalysts, e.g., Ag, leads to promising results.
A Dynamic Simulation Tool for the Battery‐Hybrid Hydrogen Fuel Cell Vehicle
Authors: Moore R. M. , Ramaswamy S. , Cunningham J. M. , Hauer K. H.
Published: October 2006

This paper describes a dynamic fuel cell vehicle simulation tool for the battery‐hybrid direct‐hydrogen fuel cell vehicle. The emphasis is on simulation of the hybridized hydrogen fuel cell system within an existing fuel cell vehicle simulation tool. The discussion is focused on the simulation of the sub‐systems that are unique to the hybridized direct‐hydrogen vehicle, and builds on a previous paper that described a simulation tool for the load‐following direct‐hydrogen vehicle. The configuration of the general fuel cell vehicle simulation tool has been previously presented in detail, and is only briefly reviewed in the introduction to this paper. Strictly speaking, the results provided in this paper only serve as an example that is valid for the specific fuel cell vehicle design configuration analyzed. Different design choices may lead to different results, depending strongly on the parameters used and choices taken during the detailed design process required for this highly non‐linear and n‐dimensional system. The primary purpose of this paper is not to provide a dynamic simulation tool that is the “final word” for the “optimal” hybrid fuel cell vehicle design. The primary purpose is to provide an explanation of a simulation method for analyzing the energetic aspects of a hybrid fuel cell vehicle.
Ultrastructure and morphometry of the alveolar lung of guinea pigs chronically exposed to diesel engine exhaust: Six month's experience
Authors: Barnhart Marion I. , Chen Shan‐Te , Salley Steven O. , Puro Henry
Published: October 2006

The impact of chronic inhalation of diesel exhaust (DE) on alveolar lung was studied in 24 Hartley guinea pigs. Groups were sacrificed sequentially at 2 weeks, 3 months and 6 months of exposure to either 750 μg or 1500 μg DE particles (DEP) per m3 along with age‐matched concurrent controls. Although qualitative ultrastructural changes were noticed during this time interval and dosage schedule, there was no evidence of pathologic changes such as fibrosis or emphysema. The cellular uptake of DEP was striking. By 2 weeks three alveolar cell types (alveolar macrophages, epithelial type 1 cells and interstitial macrophages) plus one type of granulocytic leukocyte (eosinophils) confined DEP within phagosomes without evidence of cytotoxicity. A certain phagosomal DEP population had a bull's eye appearance and diameters of 0.0727 ± 0.01 μm. Morphometric analysis applied to electron micrographs demonstrated that arithmetic mean tissue thickness of the air–blood barrier was generally increased (p < 0.05) during DE exposure. For the 750 μg DE sets, the increase over control (1.56 μm) was 41% at 2 weeks, 46% at 3 months and 77% at 6 months while the 1500 μg DE set at 6 months exceeded control by 130%. Increases in absolute tissue volumes of interstitium and epithelial type 2 cells largely accounted for the increased tissue thickness. Harmonic mean tissue thickness for controls remained near 0.537 ± 0.03 μm for the study interval, contrasting with values for 3 and 6 month 750 μg DE and 6 month 1500 μB DE sets which increased. However, the diffusion capacity of the lung determined morphometrically was not decreased in DE exposed sets. Although cellular uptake of DEP and increased prominence of secretory epithelium were dose/duration related, absence of linearity suggests adaptative responses.
The effects of five weeks treatment with dinitro‐o‐cresol‐ or trifluralin‐containing pesticides on the germ cells of male mice
Authors: Nehéz M. , Selypes A. , Páldy A. , Mazzag E. , Berencsi G. , Jármay K.
Published: October 2006

The effects of two pesticides, the insecticide‐herbicide Krezonit E, which contains 50% dinitro‐o‐cresol, and the herbicide Olitref, which contains 26% trifluralin (2,6‐dinitro‐N.N ‐dipropyl‐4‐trifluoromethylaniline), on the gonads and germ cells of male mice were studied. The pesticides were given twice a week for 5 weeks in i.p. doses of 0.6 mg kg−1 for Krezonit E and 6.0 mg kg−1 for Olitref. These doses are 1% of the i.p. LD50. Cytogenic analysis of germ cells carried out from 3 weeks onwards after the last treatment day showed that Olitref significantly increased the frequency of germinal chromosomal abnormalities at 6–7 weeks after treatment. This pesticide increased the frequency of autosomal univalents X/Y separations at meiotic metaphase and multivalent configurations. Krezonit E did not increase significantly the number of chromosomal abnormalities, although there was some increase at 3 weeks, mainly in the form of autosomal univalents.
An in vitro model of alcohol and acetaldehyde teratogenicity
Authors: Thompson P. A. C. , Folb P. I.
Published: October 2006

C3H mouse embryos were supported in an in vitro culture system over 28‐h periods between 8 and 10 days post‐conception. Morphological development over this critical period of organogenesis was monitored in the following respects: somite count; presence or absence of heart beat; central nervous system size and symmetry; neural tube fusion. Total embryo DNA synthesis, determined by 3H‐thymidine uptake of the embryo over the last 4 h of the culture period, was compared with morphological findings. The effects of varying concentrations of ethanol and acetaldehyde, respectively, on morphology and DNA synthesis were determined at the dose levels tested. Both ethanol and acetaldehyde were toxic to the mouse embryos at this stage of their development, and reasonably close correlation was found between morphological abnormalities and reduction in DNA synthesis.
Comparison of somatic and germ cell models for cytogenetic screening
Authors: Holden Henry E.
Published: October 2006

A variety of in vivo mammalian test models are available for screening of chemicals for mutagenicity at the chromosomal level. These models have been grouped into those focusing on somatic cell effects and those dealing with germ cell effects. An analysis of available literature indicates that 76 compounds have been tested from chromosome effects in both somatic and germ cells. Of these, concordant results (positive–positive or negative–negative) were obtained with 58 compounds. Of the remaining 18 compounds with discordant results, all were positive in somatic cells, but negative in germ cell assays. These results suggest an inherent relative insensitivity of germ cells themselves to mutagenic chemicals. In the context of screening for safety evaluation purposes, this analysis suggests that a negative somatic‐cell response can be taken as highly predictive of negative results in a germ cell assessment.
Inhibition of human erythrocyte and plasma cholinesterases by methamidophos
Authors: Robinson Casey P. , Beiergrohslein Donald
Published: October 2006

Methamidophos (O, S‐dimethyl phosphoramidothioate) inhibition of human erythrocyte and plasma cholinesterase was studied in vitro. The pseudo‐biomolecular rate constant of inhibition was 3.14 ± 0.22 × 103 M−1 min−1 for erythrocyte cholinesterase and 1.85 ± 0.01 × 103 M−1 min−1 for plasma cholinesterase. Thus methamidophos, although quite toxic to mammals, is a slow, rather non‐selective inhibitor of human cholinesterases, as was also observed previously in rats.
Hepatic effects of orally administered styrene in rats
Authors: Srivastava S. P. , Das Mukul , Mushtaq M. , Chandra S. V. , Seth Prahlad K.
Published: October 2006

Adult male rats receiving styrene by gavage (200 or 400 mg kg−1, 6 days a week) for 100 days exhibited a significant dose‐dependent increase in hepatic benzo[a]pyrene hydroxylase and ammopyrine‐N‐demethylase, a decrease in glutathione‐S‐transferase and no change in glucose‐6‐phosphatase. A decrease in the activity of mitochondrial succinic dehydrogenase and β‐glucuronidase was also observed. Activity of acid phosphatase was decreased only at the higher dose level. Levels of serum glutamic oxaloacetic transaminase and glutamic pyruvic transaminase were elevated only at the higher dose level. The absolute and relative weights of the liver of control and treated animals showed no significant difference. Histopathological studies of the liver tissue revealed tiny areas of focal necrosis, consisting of few degenerated hepatocytes and inflammatory cells at the higher dose level only.
Parameters affecting the mutagenic activity of cigarette smokers' urine
Authors: Recio Leslie , Enoch Harry , Hannan M. A.
Published: October 2006

Cigarette smoke is a complex chemical mixture which displays a number of biological activities including mutagenesis. The absorption of smoke components by the lungs results in their systemic distribution, which then leads to the presence of mutagens in the urine. The detection of mutagenic substances in the urine by short‐term bioassays has been suggested for use in monitoring human exposure to various carcinogenic/mutagenic substances. In this connection, we felt that further studies on the mutagenic activity present in cigarette smokers' urine were needed. In the present studies, the dose–response relationship between the number of cigarettes smoked versus urine mutagenic activity and the persistence of mutagens in the urine after the cessation of smoking have been examined. The studies were carried out on a group of smokers and non‐smokers in Lexington, Kentucky. Although a dose–response relationship (urine mutagenicity versus the number of cigarettes smoked per day) was not observed in the group of smokers assayed, a linear dose–response relationship was detected in an individual smoker who smoked a varying number of cigarettes over eight successive days. In another smoker who ceased smoking, mutagens were detected in the urine for one week. The urine mutagenicity data from a group of smokers and non‐smokers should prove useful in extending this technique to the monitoring of other environmental exposure.
Non‐mutagenicity of 2‐Methyl‐2,3‐Epoxybutane and factors influencing the mutagenicity of 2,3‐Epoxybutane
Authors: De Meester C. , Mercier M. , Poncelet F.
Published: October 2006

The compound 2,3‐epoxybutane (2,3‐EB) is a direct mutagen for the base‐pair‐substitution‐sensitive strains TA 1530, TA 1535 and TA 100, in the absence and in the presence of metabolic activation by liver S9‐mix. Under the same experimental conditions, the 2‐methyl derivative of 2,3‐EB was not mutagenic, up to 10 mg per plate. The parent compound (2,3‐EB) was more active on strain TA 1530 in the presence of liver S9‐mix. This was observed at every epoxide concentration tested. The increase of mutagenicity depended on the S9 concentration, the mix composition and to a small extent on the method utilized.
Subjective symptoms in workers with low‐level exposure to lead
Authors: Fischbein Alf , Thornton John C. , Sarkozi Laszlo , Kon Steven , Levin Stephen
Published: October 2006

In an attempt to identify health effects associated with low‐level lead exposure, 45 cable‐manufacturing workers underwent clinical examinations in a cross‐sectional study. Thirteen workers were in direct contact with lead‐containing stabilizers, while 31 were only indirectly exposed. The directly exposed had a higher prevalence of reported neurological and gastrointestinal symptoms than those with low or insignificant lead exposure. None of the directly exposed had blood lead levels exceeding 60 μg per 100 ml. The clinical symptoms correlated with blood lead and zinc protoporphyrin. However, when the data were subjected to hierarchical log–linear modeling, a partial association was found between zinc protoporphyrin and symptoms, but not between blood lead and symptoms. The data suggest that non‐specific neurological and gastrointestinal symptoms may occur at relatively low blood lead and zinc protoporphyrin levels, and that measurement of zinc protoporphyrin and exploration of clinical symptoms are valuable components in lead screening programs.
Toxic alkaloids and their interaction with microsomal cytochrome P‐450 in vitro
Authors: Peeples A. , Dalvi R. R.
Published: October 2006

Studies on the binding spectra of certain alkaloids with rat liver microsomes revealed that brucine, scopolamine and strychnine are type I compounds, whereas boldine, emetine, nicotine, reserpine and sanguinarine show type II binding. In contrast, colchicine and solanine failed to produce any measurable binding spectra. In vitro incubation of colchicine, nicotine or scopolamine with microsomal suspensions and NADPH resulted in demethylation of these alkaloids, while the incubation of boldine, brucine, emetine, reserpine, sanguinarine or solanine showed little or no dealkylation reaction. Furthermore, the effect of these alkaloids on the in vitro microsomal metabolism of a drug, benzphetamine, has also been studied.
Blood levels of caffeine and results of fetal examination after oral administration of caffeine to pregnant rats
Authors: Ikeda George J. , Sapienza Philip P. , McGinnis Marcy L. , Bragg Lois E. , Walsh John J. , Collins Thomas F. X.
Published: October 2006

Pregnant FDA‐strain Osborne–Mendel rats were administered repeated doses of caffeine by oral intubation (gavage) and by administration in the drinking water (ad libitum sipping). When [1‐methyl‐14C] caffeine was administered at a dosage of 80 mg per kg per day by ad libitum sipping on days 12 to 15 of gestation, the amounts of radioactivity in blood were variable; the highest level on day 12 was 0.2% of the dose per ml of blood. The highest blood level of caffeine observed during a 24‐h sampling period averaged 5.7 μg ml−1. When [14C] caffeine was administered by gavage at a dosage of 80 mg kg−1 on day 12, the blood level of radioactivity reached a peak of 0.4% of the dose per ml of blood and declined rapidly thereafter. The highest amount of caffeine observed in blood averaged 63.1 μg ml−1, 1 h after gavage. The overall blood elimination half‐life of radioactivity in pregnant rats treated by gavage was 2.6 h, and the half‐life of caffeine in blood was 1.7 h. The levels of radioactivity in the fetus and maternal muscle per unit weight were comparable after each method of administration. A comparison of autopsy results from both groups indicated that resorptions were increased when compared with rats that did not receive caffeine; this effect was more marked in the gavage group than in the ad libitum sipping group. Ectrodactyly was observed only in offspring of the gavage group. The incidences of ectrodactyly or resorptions did not appear to be directly related to nutrition or fluid intake.
Urinary mercapturic acid in chemical workers and in control subjects
Authors: Buffoni F. , Santoni G. , Albanese V. , Dolara P.
Published: October 2006

Mercapturic acid urinary excretion was followed in a control group and in chemical workers exposed to toxic and mutagenic compounds. Chemical workers had a significantly lower excretion of mercapturic acid when compared with controls. Smoking effects were not significant statistically. No correlation was found between urinary mutagenic activity and mercapturic acid urinary excretion.
Acetaminophen and its toxicity
Authors: Savides Michael C. , Oehme Frederick W.
Published: October 2006

Acetaminophen (APAP) is considered one of the safest of all minor analgesics, but when taken in large doses (>10g) toxicity occurs. Severely poisoned patients experience hepatic and/or renal failure. The major metabolic pathway of APAP is formation of glucuronide and sulfate conjugates. A minor pathway is formation of a reactive metabolite that conjugates with glutathione (GSH). When GSH is depleted, the reactive metabolite causes necrosis of hepatic and other tissues. Treatment of APAP toxicity involves supplying alternate sulfhydryl donors or inhibiting oxidative formation of the reactive metabolite. Estimation of plasma APAP levels is necessary for effective treatment.
Embryotoxicity of sixteen industrial amines to the chicken embryo
Authors: Korhonen A. , Hemminki K. , Vainio H.
Published: October 2006

Sixteen amine compounds that are used in the rubber industry, and sodium nitrite, were tested on three‐day chicken embryos for embryotoxicity. The parameters measured were: early deaths recorded within two days of injection, late deaths of malformed embryos, late deaths of non‐malformed embryos and malformed survivors. The most embryotoxic chemicals were N‐phenyl‐N′‐isopropyl‐p‐phenylenediamine, N,N,N,‐triethylethylenediamine, N,N′,‐dicyclohexyl‐p‐phenyleneamine and triethylamine, with total effect ED50 values, including deaths and malformations, between 0.11 and 0.90 μmol per egg. The ED50 values for triethylenetetramine, N‐(1,3‐dimethylbutyl)‐N′‐phenyl‐p‐phenylenediamine, triethanolamine, N‐phenyl‐2‐naphtylamine, aniline and N‐nitrosodiphenylamine ranged from 1.1 to 7.0 μnol per egg. Sodium nitrite was the least potent, with an ED50 of 22 μmol per egg. Six chemicals produced no effects. They probably did not reach the embryo. The four most potent chemicals, together with aniline, caused the highest frequencies of malformations.
Binding of silicic acid by proteins and its relation to toxicity of silicate dusts
Authors: Misra Virendra , Rahman Qamar , Viswanathan P. N.
Published: October 2006

A possible mechanism of biological effects of silicate dusts is the interaction between silicic acid and tissue constituents, and this has been studied in vitro. On incubating silicic acid with lung homogenate, appreciable amounts of silicon were recovered in the trichloroacetic acid precipitate in both organic solvent extract and residual protein. Polyvinyl pyrrolidone inhibited this interaction as well as reducing the dissolution of silicic acid from asbestos dust. The capacity of serum albumin to bind silicic acid was also observed. Chemical interaction between macromolecules and silicic acid could be one of the factors responsible for the biological effects of silicon—containing dusts.
Effects of partial hepatectomy on organ‐specific toxic response to 1,2‐dibromo‐3‐chloropropane (DBCP)
Authors: Kluwe William M.
Published: October 2006

The organ‐specific toxic potency of subcutaneously administered 1,2‐dibromo‐3‐chloropropane (DBCP) was compared in partially hepatectomized and sham‐operated rats over a dose range of 20–80 mg kg−1 to assess the roles of hepatic and extrahepatic metabolism in protection against acute renal and gonadal injury. Relative kidney weight and the severity of DBCP‐induced renal proximal tubular cell necrosis were increased in rats subjected to a partial (70%) surgical hepatectomy 48 h prior to treatment with DBCP at 80 mg kg−1. Relative liver weight was reduced by DBCP in the hepatectomized, but not in the shamoperated, rats. The severity of DBCP‐induced (80 mg kg−1) hepatocellular centrilobular necrosis was greater in hepatectomized than in sham rats. DBCP reduced the relative weights of the testis and epididymis in a progressive manner and produced dose‐dependent seminiferous tubular atrophy within 12 days of treatment. The morphologically apparent lesions of the testis and epididymis were enhanced by hepatectomy. The concentration of non‐protein sulfhydryl groups (NPS) in rat liver was increased by partial hepatectomy. Because of the resulting decrease in liver size, however, the total amount of hepatic NPS per kg body weight 48 h post‐surgery was lower than in sham rats. The surgery had no effect on renal, testicular or epididymal NPS concentrations or organ weights. Partial hepatectomy greatly increased pentobarbital and ethanol sleeping times, while sleep induction time for pentobarbital was decreased. These results are consistent with previous studies indicating that the metabolism of DBCP and conjugation with glutathione in the liver protects extrahepatic organs from toxic insult. Moreover, since extrahepatic toxicity was still evident, and often enhanced, after partial hepatectomy, extrahepatic necrogenic or cytotoxic responses would not appear to be dependent on hepatic metabolism of DBCP to a direct toxicant.
A comparative kinetics study of monochloramine and hypochlorous acid in rat
Authors: Abdel‐Rahman M. S. , Waldron D. M. , Bull R. J.
Published: October 2006

The problem of trihalomethane formation now exists with the use of chlorine (technically, a mixture of HOCl and OCl−, depending on pH) as a disinfectant in drinking water. Monochloramine (NH2Cl) may be considered as an alternative to HOCl as a disinfectant in public water supplies. This study was conducted to compare the kinetics of NH236Cl with HO36Cl in rats. The peak plasma levels of 36Cl occurred at 8 and 2 h for NH236Cl and HO36Cl, respectively. The distribution of NH236Cl and HO36Cl was highest in plasma, while the lowest activity was observed in the fat. The half‐life for 36Cl absorption was 2.49 and 2.16 h, while the elimination from plasma was 38.8 and 44.1 h after oral NH236Cl and HO36Cl treatment, respectively. Urinary excretion accounted for most of the 36Cl eliminated in both treatments.
Metabolic activation, detoxification and transformation studies with benzo[a]pyrene using rat and hamster organ cells in vitro
Authors: Raineri R. , Hillesund T. , Ernst M. K. , Cavanaugh D. M. , Poiley J. A.
Published: October 2006

The metabolism of benzo[α]pyrene (BP) by cultured kidney, liver, small intestine, lung and trachea from male Syrian golden hamsters and Sprague‐Dawley rats was compared. The metabolic capacity of intact cell systems was assessed by determining the formation of organic‐solvent‐soluble and water‐soluble metabolites, levels of covalent binding and levels of BP metabolites following separation using high‐pressure liquid chromatography. Hepatocytes from both species metabolized three to four times more BP than the other cells studied. Formation of water‐soluble metabolites by hepatocytes was at least 10 times that of the other cell types. Generally, hamster cells had greater metabolic capability than rat cells. Levels of covalent binding of metabolites of BP were at least 10 times greater in hepatocytes (uninduced) from both species than in the other cell types. Binding to hepatocytes and hamster embryo cells increased with incubation time coinciding with an increase in the formation of water‐soluble and diol metabolites. High levels of water‐soluble metabolites accompanied high levels of covalent, whole‐cell binding. Hamster embryo cells are transformed by BP without an exogenous metabolic activation system. The presence of hamster and rat hepatocytes inhibited transformation of hamster embryo cells by BP. This inhibition of transformation correlated with the increased rate of formation of water‐soluble detoxification metabolites by hepatocytes from both species. The high rate of formation of water‐soluble products by intact hepatocytes reflects the in vivo activity of liver cells. Use of hepatocytes in short‐term tests allows a system for carcinogen metabolism more closely representing that which is present in the whole animal.