bluuebunny/crossref_metadata_2025 huggingface dataset:
An investigation of the main mutagenic components of a carcinogenic oil by fractionation and testing in the modified ames assay
Authors: Ingram A. J. , Scammells D. V. , May K.
Published: October 2006

A low‐viscosity carcinogenic oil was extracted with dimethylsulphoxide (DMSO) and the extract fractionated into 1–3 ring aromatic components, 4–6 ring polycyclic aromatic compounds (PCAs) and polar materials. Each of these fractions was tested in the Mobil modified Ames assay at the same concentration as in the DMSO extract, alongside unfractionated DMSO extracts from the same oil and two reference oils. In addition the fractions were combined in various ways to examine inhibitory or additive effects.

Clear positive findings were obtained with the DMSO extract of the main test oil, with some reduction in activity in a sample (the starting material for fractionation) that was back‐extracted to remove DMSO. Of the three fractions tested on their own and assessed in terms of mutagenicity index, the 1–3 ring aromatic fraction had the greatest mutagenic activity, showing similar activity to the starting material, whereas the 4–6 ring PCA fraction had much lower activity and the polar fraction showed the lowest activity with an absence of doubling in one of the tests.

The polar fraction showed signs of an inhibitory effect on the response to the 1–3 ring aromatic fraction and to a questionable extent on that of the 4–6 ring PCA fraction. Although a low level of the 4–6 ring PCA fraction showed some inhibitory effect on the response to the 1–3 ring aromatic fraction, a low level of the 1–3 ring aromatic fraction added to the 4–6 ring PCA fraction enhanced the response.

It was concluded that 4–6 ring PCAs were not the main mutagenic components of the oil examined and that therefore the mutagenic components may be different from the carcinogenic components. It was recognized, however, that there is a need for further data on the carcinogenicity of oil fractions, particularly relating to 1–3 ring aromatic compounds.
Evaluation of three antidotes on arsenic toxicity in the common earthworm (Lumbricus terrestris)
Authors: Li Wei , Chien Paul K. , Furst Arthur
Published: October 2006

The common earthworm (Lumbricus terrestris) is being evaluated in our laboratories as a substitute for mice in metal toxicity studies. These two disparate species have enzymes in common, such as catalase, superoxide dismutase and glutathione‐S‐transferase. Also, worms respond similarly to these rodents for selenium and nickel toxicity. Worms are less sensitive, however, to metal toxicity. In this study earthworms were challenged with three different arsenic compounds: arsenite, arsenate and the vesicant phenyldichloroarsine (PDA). The median lethal dose for each arsenic compound was determined. The order of toxicity of the arsenic compounds to the worms was PDA > arsenite > arsenate (24 h LD50 values were 189.5, 191.0 and 519.4 μmol kg−1, respectively). Individual mammalian dithiol antidotes, namely the sodium salt of 2,3‐dimercapto‐1‐propanesulfonic acid (DMPS), meso‐dimercaptosuccinic acid (DMSA) or 2,3‐dimercapto‐1‐propanol (BAL), were injected into the worms 5 min after various doses of the arsenic compound were administered. The decreases in acute toxicity values were recorded. All three antidotes protected the worms against arsenic toxicity with varying degrees of effectiveness. The protective action for the inorganic arsenic compounds was in the order DMPS > DMSA > BAL. For the organic arsenical, PDA, the most effective antidote was BAL.
Effects of single or repeated administration of a carbamate, propoxur, and an organophosphate, DDVP, on jejunal cholinergic activities and contractile responses in rats
Authors: Kobayashi Haruo , Sato Itaru , Suzuki Tadahiko , Matsusaka Naonori , Yuyama Akira , Akatsu Yasuhiko , Fujii Shin‐Ichiro
Published: October 2006

Wistar rats were injected once or repeatedly for 10 days with dichlorvos (DDVP, 5 mg kg−1), propoxur (10 mg kg−1), oxotremorine (0.1 mg kg−1) or atropine (5 mg kg−1). Animals were killed 20 min or 24 h after single or consecutive injections, respectively, for determinations of cholinergic activities and contractile responses to acetylcholine (ACh) of the jejunum. Single treatments: while DDVP and propoxur decreased acetylcholinesterase (AChE) activity, oxotremorine and atropine did not. Although DDVP, propoxur and oxotremorine increased levels of ACh, atropine decreased them. Contractile responses to ACh were enhanced by DDVP and reduced by oxotremorine and atropine. The Bmax value of binding of [3H]quinuclidinyl benzylate (QNB) to muscarinic ACh receptors was decreased by atropine. Consecutive treatments: DDVP and oxotremorine decreased AChE activity markedly and slightly, respectively. Although DDVP and oxotremorine increased levels of ACh, propoxur decreased them. Without affecting the contractile responses, DDVP caused a reduction and propoxur and atropine caused an increase in the Bmax value for binding of [3H]QNB. Both the contractile responses and the value of Bmax for binding of [3H]‐QNB were decreased by oxotremorine. In summary, propoxur and DDVP showed similar effects mainly through their anticholinesterase properties in the case of single injection, but DDVP had similar effects to those of oxotremorine and propoxur had similar effects to those of atropine in the case of repeated injection.
Distribution and urinary excretion of aluminium injected with several organic acids into mice: Relationship with chemical state in serum studied by the HPLC‐ICP method
Authors: Maitani Tamio , Kubota Hiroki , Hori Natsuko , Yoshihira Kunitoshi , Takeda Mitsuharu
Published: October 2006

The correlation between the in vivo tissue distribution or the urinary excretion of aluminium (Al) administered with four organic acids and the in vitro binding of Al to serum protein in the presence of the organic acids was studied. Aluminium was injected intraperitoneally into mice with an organic acid at a dose of 20 mg Al kg−1 (Al:ligand= 1:1 or 1:3). When the Al‐citrate mixture was administered, hepatic and renal concentrations of Al at 3 h were low, while hepatic Al concentrations for the other three organic acids (malate, tartrate and isocitrate) were considerably higher. Compared to the sole administration of Al, urinary excretion of Al was at a high level in all organic acids. Aluminium added in vitro to control serum as an Al‐citrate mixture was present only in a low‐molecular‐weight (LMW) fraction, while Al added with other organic acids was present in both the high‐molecular‐weight (HMW) and LMW fractions. Consequently, it was interpreted that Al in the LMW fractions was excreted into the urine and that a significant part of Al in the HMW fractions was transferred to the liver. The binding status of Al in serum observed in the in vitro study was also manifested in the in vivo samples obtained after the intravenous injection.
Effects of atrazine on reproductive performance in the rat
Authors: Šimić Branimir , Kniewald Jasna , Kniewald Zlatko
Published: October 2006

The effects of subacute exposure to atrazine on body weight, ovarian cycling, conception rate and the size of litters in Fischer strain rats were studied. An atrazine dose of 120 mg kg−1 body wt given p.o. daily for 7 days to both female and male rats caused statistically significant loss of body weight in both sexes during the period of treatment. After the cessation of treatment the body weight of female rats remained below control body weights at least for 2 weeks. In male rats the difference in body weights narrowed with time and reached control level 5 days after the last dose. Atrazine caused a significant increase in the relative weights of pituitary and prostate. Atrazine also transiently prolonged the oestrous cycle, characterized by extended vaginal dioestrus. As a result of disturbed ovarian cycling, the rate of successful mating decreased in the first week after treatment when both sexes were exposed or exposed females were mated with an unexposed male. No similar effect was observed when only the males were exposed. The size of litters did not differ significantly between experimental groups.
Urinary selenium excretion in workers with low exposure to mercury vapour
Authors: Ellingsen Dag G. , Nordhagen Hans P. , Thomassen Yngvar
Published: October 2006

Urinary selenium excretion was studied in 21 mercury vapour (Hg°)‐exposed workers involved in the demolition of a chloralkali plant. The subjects had no known previous occupational exposure to mercury. Their mean pre‐exposure urinary mercury concentration, determined on average 1.2 days prior to the exposure, was 0.8 nmol mmol−1 creatinine (range 0.3–1.9). Their last mean urinary mercury concentration, determined on average after 51.4 days (range 19–103) of exposure, was 4.8 nmol mmol−1 creatinine (range 1.2–10.0). The exposure ceased on average 4.1 days after the last determined urinary mercury concentration. The corresponding concentrations of urinary selenium decreased from an average of 39.1 nmol mmol−1 creatinine (range 13.9–89.5) to 29.0 nmol mmol−1 creatinine (range 10.1–52.9) (P = 0.002). This finding may indicate that even a low to moderate work‐related exposure to Hg° may reduce the urinary selenium concentration in humans in a manner that is not yet fully known.
Detection of polycyclic aromatic hydrocarbon exposure damage using different methods in laboratory animals
Authors: Winker N. , Weniger P. , Klein W. , Ott E. , Kocsis F. , Schoket B. , Körpert K.
Published: October 2006

Benzo[a]pyrene, benzo[b]fluoroanthene and dibenzo[a, h]anthracene dissolved in a 1:2 mixture of dimethylsulphoxide (DMSO) and water were administered to two groups of female mice, each group containing 15 mice. The doses were administered orally (via gavage) at the respective rates of 1 and 100 μg kg−1 body weight five times per week for a period of 9 weeks. The influence of the polycyclic aromatic hydrocarbons (PAHs) was determined using the following methods: determination of DNA‐PAH adducts, of chromosome injuries (micronucleus test), of induction of repair using the unscheduled DNA synthesis (UDS) test, and by examination of the DNA structure after nucleoid sedimentation. All the methods investigated provided evidence of a significant effect resulting from exposure to PAHs on the parameters examined. Following chronic exposure to PAHs, the formation of DNA‐PAH adducts and injury to the genetic material, as well as the appearance of micronuclei (micronucleus test), the induction of unscheduled DNA synthesis (UDS test) and mutation of the DNA structure (nucleoid sedimentation), were demonstrated. The described methods therefore provide a means for the detection of genetic damage caused by PAH exposure in humans.
Effect of prior, low‐level cadmium exposure in vivo on metallothionein expression in cultured lymphocytes
Authors: Stennard Fiona A. , Stewart Tim C. , West Adrian K.
Published: October 2006

Exposure to cadmium (Cd) is currently monitored by measurement of the metal in blood or urine, or by observation of excreted compounds such as β2‐microglobulin or N‐acetyl‐β‐D‐glucose. Whilst these approaches are useful for the detection of acute exposure to Cd, their applicability in the management of long‐term, low‐level exposure is less clear. Metallothioneins are ubiquitous proteins that are synthesized in response to heavy metal ions and may offer themselves as being a biologically sensitive indicator of Cd exposure. We have examined both basal and Cd‐induced metallothionein mRNA levels in cultured lymphocytes from groups with different exposures to Cd, attempting to assess their potential as an indicator of Cd exposure and the suitability of such an assay for routine analysis. We found that induced metallothionein mRNA levels, rather than basal mRNA levels, increased in groups known to have received elevated body burdens of Cd, although these increases were not significant between groups. There was, however, a significant correlation between induced metallothionein mRNA levels and urinary β2‐microglobulin. These results suggest that further work on the in vitro lymphocyte response to Cd as a diagnostic tool is warranted.
Isopropanol: Acute vapor inhalation neurotoxicity study in rats
Authors: Gill Michael W. , Burleigh‐Flayer Heather D. , Strother Dale E. , Masten Lawrence W. , McKee Richard H. , Tyler Tipton R. , Gardiner Thomas H.
Published: October 2006

Five groups of 25 Fischer 344 rats of each sex were exposed for 6 h to isopropanol vapor at 0, 500, 1500, 5000 or 10000 ppm. Behavioral observations for 10 rats of each sex were made prior to and 1, 6, and 24 h after exposure. Motor activity was evaluated for 15 rats of each sex prior to and immediately following exposure. Exposure to isopropanol caused a spectrum of transient effects indicative of narcosis at 10000 ppm and sedation at 5000 ppm. Prostration or severe ataxia, decreased arousal, slowed or labored respiration, decreased neuromuscular function, hypothermia and loss of reflex function were observed 1 and 6 h after exposure to 10000 ppm isopropanol vapor. Similar, but less severe, alterations were observed in animals in the 5000 ppm exposure group 1 h after exposure. Exposure concentration‐related decreases in motor activity were observed in males and females in the 5000 and 10000 ppm groups and slight decreases in motor activity were observed in males in the 1500 ppm group. Animals in the 1500 and 5000 ppm exposure groups recovered from these motor activity effects within 5 h. Based on this study, exposure of male and female rats to isopropanol vapor produces transient, concentration‐related narcosis and/or sedation at concentrations of 5000 and 10000 ppm and minor decreases in motor activity in males at a concentration of 1500 ppm. The no‐observed‐effect level (NOEL) for this was 500 ppm isopropanol.
An in vitro method for determination of tissue partition coefficients of non‐volatile chemicals such as 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin and estradiol
Authors: Murphy John E. , Janszen Derek B. , Gargas Michael L.
Published: October 2006

The development of an in vitro vial equilibration technique for determining tissue and liquid partition coefficients for non‐volatile chemicals is described. Radiolabeled chemical dissolved in propylene carbonate is equilibrated with tissues or liquid at 37°C in a vial system. The solvent must be essentially immiscible with the test material. The amount of chemical movement to the tissue or liquid is compared to an appropriate reference vial, and tissue or liquid:solvent partition coefficients are calculated.

Tissue:solvent values divided by blood:solvent values provide tissue:blood partition coefficients required for developing physiologically based pharmacokinetic models for chemicals. These models are useful for estimating internal tissue doses to assess human risk from exposure to chemicals. Partition coefficients for various rat tissues, 0.9% saline solution and olive oil were determined in this study for radiolabeled 2,3,7,8‐tetrachloro‐dibenzo‐p‐dioxin (TCDD) and for the less fat‐soluble compound, estradiol. The TCDD tissue:propylene carbonate partition coefficients were found to be: blood, 0.091; fat, 17.02; liver, 0.419; brain, 0.632; kidney, 0.305; muscle, 0.408. For estradiol, the tissue:propylene carbonate partition coefficients were: blood, 0.286; fat, 0.169; liver, 1.032; brain, 0.554. The TCDD results compared well with values reported and estimated from a more protracted in vivo approach. Thus, this current technique offers a simpler and time‐saving alternative to in vivo approaches for determining the partition coefficients of non‐volatile compounds.
Evaluation of coal liquids derived from the eds process in carcinogenesis screening tests
Authors: McKee R. H. , Traul K. A. , Przygoda R. T.
Published: October 2006

Four process streams derived from the EDS

EDS is a designaiton for a direct coal liquefation process and was descriptive of an early stage in process development.

direct coal liquefaction process were evaluated in two in vitro assays to screen for carcinogenic potential: the Salmonella/mammalian microsome mutagenicity assay and the Syrian hamster embryo morphologic transformation assay. Three high boiling liquids (two recycle solvents, nominal boiling range 200–425°C; and a fuel oil blend, nominal boiling range 200–538°C) were active in both assays. A hydrotreated naphtha sample (<200°C) was not active in either. The Salmonella data agreed qualitatively with results of dermal carcinogenesis studies; however, quantitative differences as measured by the estimation of mutagenic potency were apparent. The lack of quantitative agreement may have been related to the fact that the dermal carcinogenic activity of coal‐derived synthetic fuels is predominantly associated with neutral polycyclic aromatic hydrocarbons, whereas activity in the Salmonella assay is strongly influenced by the presence of aromatic amines and nitroaromatic compounds.

Two modifications of the Salmonella assay—detergent disperson and hamster S9 activation—were examined. These techniques improved assay performance for some but not all of the coal liquids. The differences in response may have been related to compositional differences in the various liquids.
Ecological hazard assessment of aqueous soil extracts using fetax
Authors: Fort Douglas J. , Stover Enos L. , Norton Dale
Published: October 2006

Frog Embryo Teratogenesis Assay—Xenopus (FETAX) testing of a series of diverse hazardous waste‐site soil samples was performed to evaluate the efficacy of FETAX as a rapid developmental toxicity screening tool for environmental hazard assessment. Soil samples were collected from six different hazardous waste sites, three from eastern and three from western Washington State. The type of waste site samples studied, based on the contaminants identified, included: heavy metals (2), polymnuclear aromatic hydrocarbons, petroleum products (2) and organochlorine pesticides. Three to five samples from each site representing baseline and increasing levels of contamination were collected. Aqueous extracts of the soil samples were prepared and used for FETAX studies. Samples collected from the polynuclear aromatic hydrocarbon‐ and petroleum product‐contaminated sites induced greater levels of embryolethal effects, although embryonic malformation was also observed. The metal‐contaminated sites induced greater levels of embryonic malformation, but induced less embryolethality than the other samples evaluated. The organochlorine pesticide‐contaminated site samples caused significant levels of embryonic deformities but failed to induce embryolethal effects. Results from these studies suggested that FETAX was sensitive enough to detect low levels of developmental toxicants but robust enough to be suitable for aqueous soil extract testing. FETAX may be used as a component of a battery of tests designed to assess potential ecological hazard.
Serum biochemical and histopathological changes related to the hepatic function in pigs following atrazine treatment
Authors: Gojmerac T. , Kartal B. , Žurić M. , Ćurić S. , Mitak M.
Published: October 2006

Biochemical and histopathological parameters of the hepatic function were used to quantify the hepatotoxic effects of atrazine in female pigs (gilts) undergoing intensive breeding. Female pigs (cross‐bred Swedish and German landrace) received 2 mg atrazine kg−1 body wt. in feed daily during 19 days of the oestrous cycle. The last treatment day corresponded to day ‐3 of the onset of the next expected oestrus: Blood samples were collected three times daily at 3‐h intervals on the first four post‐treatment days. Serum activities of γ‐glutamyltransferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (AP) were determined. Serum activity of GGT was significantly increased throughout the four post‐treatment days. In comparison with the control values, a slight but not significant decrease was observed in the serum activities of ALT, AST and AP. Histopathological examination of the liver of exposed pigs showed mild centrolobular parenchymatous degeneration. Interstitial connective tissue proliferation resulted in narrow and irregular bile canaliculi.
Effect of 2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin on the Hepatic Distribution of Iron, Copper, Zinc, and Magnesium in Rats
Authors: Wahba Z. Z. , Al‐Bayati Z. A. F , Stohs S. J.
Published: October 2006

The distribution of iron, copper, zinc, and magnesium in hepatic subcellular fractions of male and female rats treated with 2,3,7,8‐tetrachloro‐dibenzo‐p‐dioxin (TCDD) was determined. Animals received 40 μg TCDD per kilogram per day for three days by mouth (PO) or the vehicle and were killed seven or nine days posttreatment. Iron, copper, zinc, and magnesium were determined by atomic absorption spectroscopy. The iron content of liver from female animals was twofold higher than male animals. The administration of TCDD increased the iron content of mitochondria in female and male rats and decreased iron content of microsomes of both sexes. Significant increases occurred in the copper content of whole liver, mitochondria, and cytosol of male rats and in whole liver and cytosol of female rats. Decreases in the copper content of the microsomes of male rats were observed following TCDD treatment; however, TCDD produced no changes in the zinc content of hepatic subcellular fractions of either sex. The magnesium content of female TCDD‐treated rats increased in whole liver, mitochondria, and cytosol, while the magnesium content of microsomes was not altered. With respect to the subcellular distribution of iron, copper, zinc, and magnesium, TCDD produces differential effects. The altered distribution of some cations may contribute to the broad range of effects of TCDD.
Purification of rat liver microsomal cytochrome P‐450b without the use of nonionic detergent
Authors: Dutton David R. , McMillen Susan K. , Parkinson Andrew
Published: October 2006

Sodium cholate, Emulgen 911, and (3‐[(‐cholamidopropyl)‐dimethyl‐ ammonio]‐1‐propanesulfonate) (CHAPS) were selected to examine the effects of ionic, nonionic, and zwitterionic detergents on testosterone hydroxylation catalyzed by four purified isozymes of rat liver microsomal cytochrome P‐450, namely P‐450a, P‐450b, P‐450c, and P‐450h, in reconstituted systems containing optimal amounts of dilauroylphosphatidylcholine and saturating amounts of NADPH‐ cytochrome P‐450 reductase (reductase). The major phenobarbital‐inducible form of rat liver microsomal cytochrome P‐450, designated P‐450b, was extremely sensitive to the inhibitory effects of Emulgen 911, which is used in several procedures to purify this and other forms of cytochrome P‐450. In contrast, sodium cholate and CHAPS had little effect on the catalytic activity of cytochrome P‐450b, even at ten times the concentration of Emulgen 911 effecting 50% inhibition (IC‐50). By substituting the zwitterionic detergent CHAPS for Emulgen 911, we purified cytochrome P‐450b without the use of nonionic detergent. The protein is designated cytochrome P‐450b* to distinguish it from cytochrome P‐450b purified with the use of Emulgen 911. NADPH‐cytochrome P‐450 reductase was also purified both with and without the use of nonionic detergent.

The absolute spectra of cytochrome P‐450b and P‐450b* were indistinguishable, as were the carbon monoxide (CO)‐ and metyrapone‐difference spectra of the dithionite‐reduced hemoproteins. When reconstituted with NADPH‐cytochrome P‐450 reductase and dilauroylphosphatidylcholine, cytochromes P‐450b and P‐450b* catalyzed the N‐demethylation of benzphetamine and aminopyrine, the 4‐hydroxylation of aniline, the O‐dealkylation of 7‐ethoxycoumarin, the 3‐hydroxylation of hexobarbital, and the 6‐hydroxylation of zoxazolamine. Both hemo‐proteins catalyzed the 16α‐ and 16β‐hydroxylation of testosterone, as well as the 17‐oxidation of testosterone to androstenedione. Both hemoproteins were poor catalysts of erythromycin demethylation and benzo[a]pyrene 3‐/9‐hydroxylation. The rate of biotransformation catalyzed by cytochrome P‐450b* was up to 50% greater than the rate catalyzed by cytochrome P‐450b when reconstituted with either reductase or reductase*. The activity of cytochrome P‐450b and P‐450b* increased up to 50% when reconstituted with reductase* instead of reductase. In addition to establishing the feasibility of purifying an isozyme of rat liver microsomal cytochrome P‐450 without the use of nonionic detergent, these results indicate that the catalytic activity of cytochrome P‐450 is not unduly compromised by residual contamination with the nonionic detergent Emulgen 911.
A study on the recovery of xylitol by batch adsorption and crystallization from fermented sugarcane bagasse hydrolysate
Authors: Mussatto Solange I , Santos Júlio C , Ricardo Filho Walter C , Silva Silvio S
Published: October 2006

Xylitol was recovered from fermented sugarcane bagasse hemicellulosic hydrolysate by adsorption and crystallization procedures. Silica gel adsorption was employed to purify the broth containing xylitol. In this step, different mixtures of the solvents ethyl acetate, ethanol and acetone were used as eluent, and different proportions of fermented broth volume incorporated per gram of silica gel (Vb/Msg, varying from 1.0 to 2.0 cm3 g−1) were used to pack the column employed as stationary phase bed. The xylitol purification efficiency varied for each mixture of solvent, and for each Vb/Msg ratio used. The purified broth was submitted to different crystallization procedures (cooling, concentration and supplementation with commercial xylitol) aiming to recover xylitol crystals. The best result (60% crystallization yield and 33% total recovery of xylitol from fermented broth) was obtained when the column was packed with a Vb/Msg ratio of 2 cm3 g−1, and the broth was purified with a mixture of ethyl acetate and ethanol, concentrated 6.5‐fold, and supplemented with commercial xylitol to force the precipitation. Copyright © 2006 Society of Chemical Industry
Novel Molecular Resist Based on a First Generation Dendrimer Possessing Furan Rings
Authors: Mori Hajime , Nomura Eisaku , Hosoda Asao , Miyake Yasuhito , Taniguchi Hisaji
Published: October 2006

Summary: A novel chemically amplified negative‐tone molecular resist for electron‐beam (EB) lithography was developed. The base matrix had six furan rings as a reactive functional group at its terminal. The resist containing the matrix, a crosslinker and a photoacid generator worked well as a negative‐tone resist with high sensitivity (3 µC · cm−2). Line and space patterns (1:2) of 200 nm could be fabricated.

SEM image of negative‐tone line and space patterns for the resist film formulated with G1‐dendrimer 5.

magnified image

SEM image of negative‐tone line and space patterns for the resist film formulated with G1‐dendrimer 5.
Modelling and numerical analysis of heat treatments on aluminium parts
Authors: Andrade‐Campos A. , Neto da Silva F. , Teixeira‐Dias F.
Published: October 2006

A theoretical model suitable for the modelling and analysis of heat treatment problems is described. The presented formulations are implemented incrementally with a non‐linear rate‐dependent constitutive model, adequate to the simulation of a wide range temperature processes. The large deformation model is based on the additive decomposition of the strain rate tensor in elastic, thermal and viscoplastic parts. The flow rule is a function of the equivalent stress and the deviatoric stress tensor of the temperature field and of a set of internal state variables. The thermal problem is solved by a prediction/correction algorithm. The prediction, which uses a semi‐implicit integration, provides a first estimation of the temperature field. The correction stage, performed with a Newton–Raphson implicit scheme, improves the solution until a satisfactory result is found. The thermomechanical coupled problem is solved with a staggered approach. The finite element formulations for coupled analysis of deformation and heat transfer given in this article are validated and applied to the process of quenching of aluminium parts into boiling water. Copyright © 2006 John Wiley & Sons, Ltd.
Experience of a premarketing alert
Authors: East M. O.
Published: October 2006

A very effective and well‐tolerated beta‐blocking agent was withdrawn from preregistration clinical development because a pattern of endocrine‐related tumours was observed in high‐dose, long‐term studies in rodents. The use of doses of up to 90 times the maximum dose in man was the result of regulatory agency insistence at that time that the maximum dose tolerated by the rodents must be used. In addition, the relevance of the differences between genotoxic and non‐genotoxic carcinogenicity to man was not fully understood or accepted. More appropriate criteria are now used to select dose levels in long‐term rodent studies, and the relevance of the differences in carcinogenicity is accepted.
Nomifensine and hemolytic anemia — experience of a post‐marketing alert
Authors: Stonier Peter D.
Published: October 2006

The antidepressant nomifensine was withdrawn worldwide by the manufacturer in January 1986 following a rising incidence of reports of acute immune hemolytic anemia with serious clinical sequelae, including a number of fatalities. This short report describes the chronology of events leading up to the drug's withdrawal in one country, the United Kingdom, 9 years after it was first made available. The known incidence of hemolytic anemia reports was related to prescription data and showed that the risk‐benefit ratio was tipped against continued availability of the drug only in the latter part of 1985, shortly before the drug was withdrawn. Factors related to the increased reporting of the adverse events are discussed, but increased awareness by prescribers of drug‐related events and their willingness to report them as a result of medical literature and media reports, including publications by the Committee on Safety of Medicines of Yellow Card data, are thought to have been major contributors.
The determinants of warfarin requirements in Chinese patients
Authors: Chan Thomas Y. K. , Tsoi W. C. , Critchley Julian A. J. H.
Published: October 2006

The warfarin requirements of 33 Chinese patients presenting with deep vein thrombosis and/or pulmonary thromboembolism were studied. The mean daily maintenance dosage was considerably lower in Chinese (3 mg) than in Caucasian subjects (4–6 mg) and, as in Caucasian subjects, the age of the patient rather than body weight was an important determinant of warfarin requirements (r = 0.4, p < 0.05).
PEM report number 6. Paroxetine
Authors: Inman William , Kubota Kiyoshi , Pearce Gillian , Wilton Lynda
Published: October 2006

Patients (13,741) who had been treated with paroxetine between March 1991 and March 1992 have been, studied by Prescription‐Event Monitoring (PEM). The events were compared with those recorded in studies of two other selective serotonin re‐uptake inhibitors (SSRIs) and with data from 31 PEM studies of unrelated drugs.

The most frequent indication was depression (94%). A daily dose of 20 mg was prescribed most frequently (93%). Benzodiazepines had been co‐prescribed for 9% of the patients. Treatment was considered to have been effective in 62% of patients.

The rates of events occurring during the first‐month of treatment were compared with the mean rates recorded during the second to the sixth month of treatment. The analysis was restricted to those events which had been experienced by 14 or more patients during the first month of treatment (rates in excess of one per 1000). A ‘signal’ was noted when this rate exceeded the second‐to‐sixth‐month rate by a factor of three or more or when the first‐month rate exceeded a pooled base‐rate for other drugs by a similar amount. All the data were compared with those obtained in earlier studies of the two SSRIs fluoxetine and fluvoxamine.

Although a number of class effects were signalled, the only noteworthy difference between paroxetine and the other two SSRIs was the rate of male sexual dysfunction which was higher for paroxetine. Several psychiatric events were recorded with greater than average frequency than in the population of 350,000 patients used for comparison, but these are all commonly associated with depressive illness. Drowsiness, insomnia and tremor were prominent side‐effects with all three drugs.

Particular attention was paid to events occurring shortly after withdrawal of paroxetine, but again, no obvious difference was detectable between these events in the three groups. This supports the view that more frequent use of the word ‘withdrawal’ may have resulted from recent publicity given to dependence, especially to benzodiazepines.

Small numbers of events of potential interest such as of disturbances of liver function, hyponatraemia, extrapyramidal signs or symptoms or convulsions were reviewed individually but no unacceptable hazards were detected.

One hundred and thirty‐seven pregnancies were followed up and no attributable abnormalities were noted.

There were 416 deaths (3%) at any time during the course of the study, of which 224 occurred during the six‐month period used in comparisons with other drugs. No deaths were atttributable to paroxetine.
PEM report number 7. Itraconazole
Authors: Inman William , Kubota Kiyoshi , Pearce Gillian , Wilton Lynda
Published: October 2006

Patients (13,645) who were prescribed the oral anti‐fungal drug itraconazole between April 1989 and April 1990 were studied by Prescription‐Event Monitoring (PEM).

The pattern of events was compared with data obtained from PEM studies of fluconazole and 31 other drugs. Upper respiratory tract and genito‐urinary infections were reported more frequently than with other drugs but the relationship was with the disease being treated rather than with the drug itself. This pattern of events was virtually identical to that which had been encountered in an earlier study of fluconazole.

Of doctors who offered an opinion, 83% considered that the drug had been effective.

A total of 340 pregnancies were recorded in this study. Although pregnancy is a contra‐indication 53 had been exposed during the first trimester. There were 40 live births including one otherwise healthy infant with a minor abnormality of one ear.

Fifty‐six of 66 deaths were successfully investigated. Cancer (27) and cardiac disease (12) were the most frequent causes of death. None was attributable to itraconazole.

One group of 114 patients with onychomycosis had been treated daily for several months without ill‐effect, suggesting a very low order of toxicity. The overall conclusion after this study of more than 13,600 patients was that most events were attributable to the candidial infection rather than its treatment and that itraconazole was virtually free from recognizable side‐effects.
PEM report number 9. Omeprazole
Authors: Wilton Lynda , Inman William , Kubota Kiyoshi , Pearce Gillian , Skipp Marilyn
Published: October 2006

Patients (16,204) who had been treated with omeprazole by general practitioners in England between June 1989 and June 1990 have been studied by Prescription‐Event Monitoring (PEM). The pattern of events recorded during the six months following each patient's initial prescription has been compared individually with four other drugs used for similar indications and studied by the same method — cisapride, misoprostol, famotidine and nizatidine — and with pooled data on these and other unrelated drugs.

Omeprazole had been prescribed most frequently for oesophageal reflux, oesophagitis, hiatus hernia and peptic ulcer or its complications. Seventy per cent of patients used a daily dose of 20 mg and 26% used 40 mg. Where efficacy had been reported, 81% of the patients were said to have benefited.

A comparison of events recorded during the first month with those recorded with other drugs produced no noteworthy ‘signals’. Diarrhoea and nausea or vomiting were the only events which produced a rate‐ratio of more than three when the rate during the first month was compared to that during months two to six. These events were probably more related to the indication than the treatment. No serious hazards were identified and no deaths were attributable to omeprazole.
The medical dictionary for drug regulatory affairs (MEDDRA) project
Authors: Wood K. L.
Published: October 2006

Electronic transmission of information is a key component of the Future System for medicines regulation in the European Union (EU). Data sets and terminology will have to be standardized in order to ensure effective information exchange between organizations. The Medical Dictionary for Drug Regulatory Affairs (MEDDRA) is a medical terminology being prepared by an international Working Party for use by regulatory authorities, pharmaceutical companies and other relevant organizations. It incorporates terms relevant to all areas of drug regulation, including the marketing authorization (MA) process, MA maintenance/renewal and pharmacovigilance.
Medical events after a prescription for a benzodiazepine
Authors: Neutel C. Ineke , Downey Winanne , Senft Dwayne
Published: October 2006

Much controversy has surrounded triazolam since it was marketed in the late 1970s. In spite of ongoing debate no major pharmacoepidiomological study has been published, comparing triazolam to other benzodiazepines (BZD). The present study examines the occurrence of medical events after a prescription for one of five BZD. Data was obtained from the Saskatchewan Health Data Bases on all persons who received a prescription for one of triazolam, flurazepam, oxazepam, lorazepam or diazepam, not having had a prescription for any of these in the previous six months. These persons were monitored for eight types of medical events. (1. suicides and attempts, 2. depression, 3. other psychiatric condition, 4. traffic accident injury, 5. injury due to falls, 6. injury due to poisoning, 7. seizures, 8. allergic reactions) for three weeks after their prescription for the BZD. Rates for medical events were compared to those in an unexposed population sample. It was concluded that, on the whole, triazolam does not appear to show a record of hospitalization worse than the other five BZD tested. In general, BZD should be used cautiously, judiciously and at the lowest possible dose.
A prospective study of adverse drug reactions to anti tuberculous drugs
Authors: Thomas Molly , Seshadri M. S. , Cherian A. M.
Published: October 2006

A study of adverse drug reactions to anti tuberculosis therapy in the medical outpatients showed that the overall incidence of adverse reactions was 26 per cent. Side‐effects to isoniazid and rifampicin were mainly hepatitis, nausea, vomiting. Ethambutol caused reversible optic neuritis in 7.9 per cent cases. Most adverse drug reactions occurred during the first 3 months of treatment.
Evolution of histamine H2‐receptor antagonist use in an ambulatory elderly population: A 14‐year overview
Authors: Stewart Ronald B. , Neal Carolyn , Padgett Phillip D. , Marks Ronald G. , Hale William E.
Published: October 2006

The purpose of this study was to determine the frequency and pattern of histamine H2‐receptor antagonist drug use in an ambulatory elderly population of individuals over 65 years of age from 1978 to 1992. A longitudinal health screening programme of ambulatory elderly participants was employed to conduct a series of cross‐sectional studies over a 14‐year period.

Participants in the first period (1978–79) included 855 (37.1%) men and 1448 (62.9%) women. The use of histamine H2‐receptor antagonist increased from 0.8% of the population in the 1978–79 period to 7.0% in the 1991–92 period. There was no statistically significant correlation between drug use and age (p = 0.8114) or sex (p = 0.9229) at the 1991–92 time period. In the 1991–92 time period, cimetidine and ranitidine combined, accounted for 86.0% of all reported histamine H2‐receptor antagonist.

Over the 14‐year period of study there has been a nearly constant increase of histamine H2‐receptor antagonist use in this elderly population.
Testing for clustering in record linkage databases
Authors: Hammerstrom Thomas
Published: October 2006

One way to identify an excess risk of an adverse event during drug exposure is to use administrative, medical, and pharmacy records data, such as Medicaid or HMO (Health Maintenance Organization) records, to compare the relative frequency of the suspect event in exposed and unexposed periods. Such estimates can be seriously biased if there is clustering in patient visits to physicians and pharmacies. This paper presents two simple tests for determining whether the patient visit dates in such a database are Poisson processes of visits or clustered processes. The paper shows that this test is quite powerful at detecting both clustered sequences and nearly regular sequences of visits. Finally, it gives a straightforward SAS program which will carry out the tests.
Use of insurance claims in epidemiologic research: Identification of peptic ulcers, gi bleeding, pancreatitis, hepatitis and renal disease
Authors: Lanza Lee L. , Dreyer Nancy A. , Schultz Nathan J. , Walker Alexander M.
Published: October 2006

Data bases that are created to administer health care benefits and to record financial aspects of medical care in the United States are useful for epidemiologic research in certain circumstances. Case finding and verification in such records is complex and rarely described in detail in research reports because of space limitations. This report describes portmarketing surveillance for peptic ulcer, upper gastrointestinal hemorrhage and hepatic dysfunction in 68, 180 people who took non‐steroidal anti‐inflammatory drugs (NSAIDs), by using an automated data base together with review of selected medical records. Cases included both mild diseases treated on an outpatient basis and more severe illnesses that required hospital admission. Using computer programs we identified 9642 subjects who had at least one insurance claim suggesting a possible case event. We manually reviewed chronological profiles of their insurance claims, to select 833 subjects for medical record reviews, of whom 152 were verified as cases. Our algorithms for case identification were sensitive, but not very specific. If we had restricted our manual review to people who had at least five relevant claims during the study period, we would have avoided 42% of the reviewing workload and lost only 5% of the cases.
Organic amendments affecting sorption, leaching and dissipation of fungicides in soils
Authors: Fernandes María C , Cox Lucía , Hermosín María C , Cornejo Juan
Published: October 2006

Metalaxyl and tricyclazole are two fungicides widely used in Spain in vineyard and rice crops respectively. In this study an investigation has been made of the effect of three organic amendments [two commercial amendments, solid fertiormont (SF) and liquid fertiormont (LF), and a residue from the olive oil production industry, alperujo (OW)] on fungicide fate in soils. Changes in soil porosity on amendment were studied by mercury intrusion porosimetry, sorption–desorption studies were performed by the batch equilibration method, dissipation of metalaxyl and tricyclazole in the soil was studied at − 33 kPa moisture content and 20 °C and leaching was studied in hand‐packed soil columns. Amendments with SF and LF reduced soil porosity, while OW increased porosity through an increase in pore volume in the highest range studied. Tricyclazole sorbed to soils to a much higher extent than metalaxyl. With some exceptions, sorption of both fungicides increased on amendment, especially in the case of SF‐amended soils, which rendered the highestKocvalues. In soils amended with the liquid amendment LF, sorption either remained unaffected or decreased, and this decrease was much higher in the case of metalaxyl and a soil with 70% clay. In this clay soil, amendment with OW, of very high soluble organic matter content, also decreased metalaxyl sorption. Tricyclazole is more persistent in soil than metalaxyl, and both fungicides were found to be more persistent in amended soils than in unamended soils. Leaching of metalaxyl and tricyclazole in soil columns was inversely related to sorption capacity. The low recoveries of tricyclazole in leachates and in soil columns when compared with metalaxyl, a less persistent fungicide, were attributed to diffusion into micropores and to increase in sorption with residence time in the soil, both processes favoured by the low mobility of tricyclazole. Copyright © 2006 Society of Chemical Industry
Synthesis, characterization and conductivity measurements of polyaniline and polyaniline/fly‐ash composites
Authors: Narayan Himanshu , Alemu Hailemichael , Iwuoha Emmanuel
Published: October 2006

Polyaniline (PANI) and polyaniline/fly ash (PANI/FA) composites with various concentrations of fly ash (20%, 40% and 50%) were synthesized by the process of in‐situ polymerization. The samples were characterized by powder X‐ray diffraction, thermogravimetric analysis, infrared spectroscopy, and scanning electron microscopy. Moreover, the dc conductivity of the samples was measured as a function of temperature in the range 80–290 K and it was found that the addition of FA decreases the conductivity. The temperature dependence of the dc conductivity for PANI and FA/PANI composites has been explained on the basis of the quasi one‐dimensional variable hopping model. A very good agreement was found between the experimental data and the theory. (© 2006 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Relationships between Octanol‐Water Partition Data, Chromatographic Indices and Their Dependence on pH in a Set of Nonsteroidal Anti‐Inflammatory Drugs
Authors: La Rotonda Maria Immacolata , Amato Gaetano , Barbato Francesco , Silipo Carlo , Vittoria Antonio
Published: October 2006

Octanol/water partition and distribution coefficients of a set of nonsteroidal anti‐inflammatory drugs were measured. Relationships between partition data at different pH values and dissociation constants are discussed.

Log k′ values were determined by reversed‐phase high‐performance liquid chromatography (HPLC) on bonded octyl and octadecylsilane supports at different pH values using various organic modifiers in the mobile phase.

The log k′ values exhibited linear relationships with methanol concentration in the mobile phase. Octanol/water partition data correlated well with the extrapolated log k′ indices to zero methanol concentration (solvent regression equations) and with the corresponding Rm indices measured on octyl and octadecyl reversed phases thin layer chromatography (HPTLC). Nature of the slopes and the intercepts of the relationships is discussed.

It is shown that the HPLC and HPTLC methods are useful alternatives for the determination of partition data.
A QSAR Study of the Ames Mutagenicity of 1‐(X‐Phenyl)‐3,3‐dialkyltriazenes Using Molecular Potential Energy Fields and Molecular Shape Analysis
Authors: Hopfinger A. J.
Published: October 2006

A set of 18 1‐(X‐phenyl)‐3,3‐dialkyltriazenes whose mutagenic potencies have been measured were investigated in terms of their potential energy fields. Molecular shape analysis, MSA, was applied to the potential energy field data and a QSAR established. The MSA descriptor, common overlap steric volume between pairs of molecules, found to be a correlate in a previous study [1] is replaced in this study by what physically appears to be the difference in dispersion binding energy between pairs of molecules. A separate investigation of the interrelationship between molecular dielectric representation and corresponding potential energy field based MSA descriptors was carried out. Single molecule MSA descriptors derived from electrostatic energetics are quite dependent on dielectric form, while corresponding pairwise difference MSA features exhibit only a marginal relationship.