bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute Neurobehavioural Effects of 2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin (TCDD) in Han/Wistar Rats
Authors: Sirkka Ulla , Pohjanvirta Raimo , Nieminen Sakari A. , Tuomisto Jouko , Ylitalo Pauli
Published: March 2009

Abstract: The neurobehavioural effects of a single non‐lethal dose (1000 μg/kg intraperitonelly) of 2,3,7,8‐tetrachlorodi‐benzo‐p‐dioxin (TCDD) were assessed in young male Han/Wistar rats, highly resistant to acute lethality of TCDD. TCDD decreased body weight significantly compared with ad libitum fed controls. TCDD did not change the behaviour or the motility of rats in the open field test 8 days after the treatment nor did it affect the spontaneous motor activity up to 27 days after the exposure. In the elevated plus‐maze test for anxiety, TCDD‐treated rats did not differ from either ad libitum fed controls or pair‐fed controls. In the 24‐hr passive avoidance test, the learning of TCDD‐treated rats did not differ significantly from that of ad libitum fed controls or pair‐fed controls from 8 hr to 16 days after the treatment. TCDD did not affect the motor coordination or the maintenance of balance on the rotating rod but it impaired them slightly in the elevated horizontal bridge test 16 hr after exposure. It did not affect nociception in the hot plate test 16 hr or 8 days after the injection. The results suggest that a single sublethal dose of TCDD does not alter markedly the general behaviour of Han/Wistar rats, in contrast to its striking effect on feeding behaviour which results in a marked decrease in body weight gain.
Single‐Dose and Steady‐State Pharmacokinetics of Diltiazem Administered in Two Different Tablet Formulations
Authors: Christrup Lona L. , Bonde Jan , Rasmussen Søren N. , Sonnergaard Jørn Møller , Jensen Bodil H.
Published: March 2009

Abstract: Single‐dose and steady state pharmacokinetics of diltiazem administered in two different oral formulations were assesed with particular reference to rate and extent of absorption. Following single dose administration a significant difference in tmax was observed (2.9 ± 1.9 and 6.8 ± 2.6 hr respectively) whereas differences in AUC, t1/2 and Cmax were not significant. The AUC (mean ± S.D.) values following single dose administration of Cardil® and Cardizem® were 678.4 ± 321.5 and 948.6 ± 580.6 ng · ml‐1 · hr respectively. The mean and the 95% confidence limits for the observed ratio AUCCardil/ AUCCardizem are 0.89 and 0.44‐1.34 respectively. At steady‐state a significant difference between Cmax/Cmin and tmax was seen Cmax/Cmin being 4.9 and 3.2 respectively and Tmax being 2.7 ± 2.0 and 6.0 ± 2.8 hr respectively, whereas Cmax and AUC did not differ significantly. The AUC (mean ± S.D.) values in steady state of Cardil® and Cardizem® were 880.1 ± 399.8 and 1056.8 ± 509.8 ng · ml‐1 · hr respectively. The mean and the 95% confidence limits for the observed ratio AUCCardil/AUCCardizem are 0.96 and 0.66‐1.26 respectively. Although the observed ratios AUCCardil/AUCCardizem in both the single‐dose and the steady‐state study do not differ significantly from 1.0, the confidence limits exceed the acceptable values given by Poulsen & Juul (personal communication 1990) (a 20% decrease or increase of the ratio to 0.8 or 1.2).
Defective Neutrophil Function in Workers Occupationally Exposed to Lead
Authors: Queiroz M. L. S. , Almeida M. , Gallão M. I. , Höehr N. F.
Published: March 2009

Abstract: Chemotaxis and niroblue tetrazolium reduction were measured in peripheral blood neutrophils of workers occupationally exposed to lead. These two neutrophil functions were significantly reduced, as compared to controls, even in those workers with blood lead levels and urinary delta‐aminolevulinic acid (ALA‐U) concentrations below the currently accepted biological limit values of 60 μ/dl and 6 mg/1, respectively. The immunosuppressive effects of relatively low level lead absorption suggests that immune dysfunction may be a sensitive indicator of lead exposure.
Cytochrome P4502A‐Mediated Cownarin 7‐Hydroxylation and Testosterone Hydroxylation in Mouse and Rat Lung
Authors: Honkakoski Paavo , Mäenpää Jukka , Leikola Junnu , Pasanen Markku , Juvonen Risto , Lang Matti A. , Pelkonen Olavi , Raunio Hannu
Published: March 2009

Abstract:Pulmonary coumarin 7‐hydroxylase, testosterone hydroxylase and other P450‐mediated activities were compared in the mouse and rat. Coumarin 7‐hydroxylase activity was 20 pmol/mg/min. in mouse and 4 pmol/mg/min. in rat lung microsomes. Liver values were 180 (mouse) and 1 (rat) pmol/mg/min. Kmvalues of rat and mouse lung coumarin 7‐hydroxylase were about 1 μM whereas the rat liver Kmvalue was > 100 μM. Phenobarbital and 3‐methylcholanthrene did not affect rat lung (or liver) coumarin 7‐hydroxylase activity. Anti‐Cyp2a‐5 antibody effectively inhibited mouse and rat lung coumarin 7‐hydroxylase and testosterone 15α‐hydroxylations but failed to block these activities in the rat liver. In immunoblot analysis anti‐Cyp2a‐5 antibody recognized the 50‐kDa Cyp2a‐4/5 protein in mouse lung microsomes. A P450 protein co‐migrating with Cyp2a‐5 was also detected in rat lung microsomes.Cyp2a‐5cDNA probe hybridized with a 1.8‐kb mRNA species in rat lung RNA fraction. The hybridization signal was not increased by 3‐methylcholanthrene or phenobarbital. These data suggest that the mouse lung expresses Cyp2a‐5 which differs from the liver enzyme only in its regulation and that the rat lung contains a P450 isoform(s) belonging to the 2A subfamily which may be orthologous with the mouse Cyp2a‐415 catalyzing coumarin 7‐hydroxylase and testosterone 15a‐hydroxylase activities. The recently reported rat lung CYP2A3 (Kimuraet al.)gene product is a candidate for the observed coumarin 7‐hydroxylase activity in the rat lung.
Binding of [3H]SCH 39166 to HumanPost MortemBrain Tissue
Authors: Hall Håkan , Halldin Christer , Sedvall Göran
Published: March 2009

Abstract:The dopamine D1antagonist SCH 39166 was labelled with tritium and used forin vitrobinding and autoradiography using humanpost mortembrain tissue. Competition studies on tissue from human nucleus caudatus showed that SCH 23390 inhibited the binding of [3H]SCH 39166 biphasically. The non‐specific binding of [3H]SCH 39166 in both nucleus caudatus and cerebellum was lower after the addition of SCH 23390 or SCH 39166 than after flupentixol (10 μM). Autoradiography showed specific [3H]SCH 39166 binding in the caudate nucleus and putamen in the brain sections. The binding of [3H]SCH 39166 in the medial part of the caudate nucleus was very dense and similar to that obtained with [3H]SCH 23390, which was used as a reference ligand. Dense binding of [3H]SCH 39166 was also found in cortical regions, and binding was also obtained in the cerebellum and in the hippocampus. Addition of flupentixol (10 μM) abolished some but not all the binding of [3H]SCH 39166. The binding of [3HJSCH 39166 to caudate and putamen was not totally abolished by the addition of excess SCH 23390, while excess SCH 39166 diminished the binding of [3H]SCH 23390 in all regions. The present study indicates that [3H]SCH 39166, similar to [3H]SCH 23390, binds to dopamine D1receptors in the human brain. It is concluded that [3H]SCH 39166 has a slightly different binding pattern than [3H]SCH 23390, which can be due to labelling of one or two additional binding site(s) pharmacologically unrelated to dopamine D1receptors.
Ventilation, CO2 Production, and CO2 Exposure Effects in Conscious, Restrained CF‐1 Mice
Authors: Nielsen Gunnar Damgård , Petersen Susanna Heissel , Vinggaard Anne Mane , Hansen Lea Frimann , Wolkoff Peder
Published: March 2009

Abstract: Respiratory rate (f), tidal volume (VT) and carbon dioxide production (VECO2) were measured in restrained, conscious CF‐1 mice. Mean f ± S.D. and mean VT ± S.D. were 270 ± 8 breaths/min. and 0.123 ± 0.024 ml (STPD) for male, and 274 ± 15 breaths/min. and 0.115 ± 0.023 ml (STPD) for female mice, respectively. VEO2 was obtained from a rebreathing (closed loop) system. The maximum VECO2 (STPD) amounted to 95.5 ± 15.4 ml/(kg min.) in males and to 72.7 ± 4.2 ml/(kg min.) in females. The CO2 concentration in the closed loop system increased slowly during a 30 min. rebreathing period and reached a concentration of about 2.7%. No effect was seen on f and on VT. Dynamic (abrupt) exposure up to 10.3% CO2 had no effect on f in male mice, whereas VT increased from 112% (2.3% CO2) to 181% (10.3% CO2). The estimated O2 concentrations decreased from 20.5% to 18.7% with increasing CO2 exposure. The equivalent CO2 experiments with O2 kept at 16% by N2 administration showed that the lower O2 concentration added an additional drive on the respiratory centre.
Relationship Between Circulating Vitamin D3 Metabolites and Prolactin or Growth Hormone Levels in Rat
Authors: Mortensen Berit , Gordeladze Jan O. , Haug Egil , Schjerven Leif , Gautvik Kaare M.
Published: March 2009

Abstract: Previous studies (Haug & Gautvik 1985) have demonstrated specific receptors for 1,25‐dihydroxyvitamin D3 (1,25(OH)2D3) in a clonal (GH3) strain of rat pituitary tumour cells. It was discovered that 1,25(OH)2D3 affected the production of prolactin and growth hormone in these cells in a calcium dependent manner. These findings were the basis for a hypothesis that vitamin D3 could be involved in the regulation of pituitary hormones in vivo. To further investigate this contention, female rats were given subcutaneous injections of 1,25(OH)2D3, 25‐hydroxyvitamin D3 (25(OH)D3) or 24,25‐dihydroxyvitamin D3 (24,25(OH)2D3) three times a week for up to 12 weeks. Blood samples were withdrawn after 28, 56 and 84 days of treatment and analysed for vitamin D, metabolites, prolactin and growth hormone, and serum ionized (free) and total calcium (Ca). Between treatment group comparisons of serum prolactin and growth hormone levels did not show significant vitamin D3 induced alterations. However, correlation matrix analyses on all variables revealed that serum level of growth hormone was significantly (P < 0.05) and inversely related to corresponding total Ca. Prolactin, on the other hand, may be subject to a complex regulation by 1,25(OH)2D3 and free Ca2+.
Clinical Application of Noradrenaline Spillover Methodology: Delineation of Regional Human Sympathetic Nervous Responses
Authors: Esler Murray
Published: March 2009

Abstract: The proportionality which in general exists between rates of sympathetic nerve firing and the overflow of noradrenaline into the venous drainage of an organ provides the experimental justification for the use of measurements of noradrenaline in plasma as a biochemical measure of sympathetic nervous function. Static measurements of noradrenaline plasma concentration have several limitations. One is the confounding influence of noradrenaline plasma clearance on plasma concentration. Other drawbacks include the distortion arising from antecubital venous sampling (this represents but one venous drainage, that of the forearm), and the inability to detect regional differentiation of sympathetic responses. Clinical regional noradrenaline spillover measurements, performed with infusions of radiolabeled noradrenaline and sampling from centrally placed catheters, and derived from regional isotope dilution, overcome these deficiencies. The strength of the methodology is that sympathetic nervous function may be studied in the internal organs not accessible to nerve recording with microneurography. Examples of the regionalization of human sympathetic responses disclosed include the preferential activation of the cardiac sympathetic outflow with mental stress, cigarette smoking, aerobic exercise, cardiac failure, coronary insufficiency, essential hypertension and in ventricular arrhythmias, and the preferential stimulation or inhibition of the renal sympathetic nerves with low salt diets and mental stress, and with exercise training, respectively. By application of the same principles, regional release of the sympathetic cotransmitters neuropeptide Y and adrenaline can be studied in humans. Cotransmitter release, however, is detected only with some difficulty. In restricted circumstances we find evidence of regional cotransmitter release to plasma, such as the release of neuropeptide Y from the heart at the very high rates of sympathetic nerve firing occurring with aerobic exercise, and cardiac adrenaline release also with exercise and after loading of the neuronal adrenaline pool by intravenous infusion of adrenaline.
Oesophageal and Gastric Potential Difference and pH in Healthy Volunteers Following Intake of Coca‐Cola, Red Wine, and Alcohol
Authors: Rubinstein Elisabeth , Hauge Christina , Sommer Peter , Mortensen Thorkild
Published: March 2009

Abstract: Alcohol causes gastroesophageal reflux and mucosal damage in the oesophagus and the stomach. The transmucosal electrical potential difference gives information on gastric mucosal integrity and function, while the validity of oesophageal measurements have been discussed. Baseline oesophageal potential difference measurements were performed three times with an interval of at least one week. We found oesophageal potential difference measurements reliable with an acceptable reproducibility. Oesophageal and gastric potential difference and pH were measured by use of a new microelectrode principle in 10 healthy volunteers following intake of coca‐cola, wine and alcohol. Oesophageal and gastric potential difference decreased after intake of 250 ml coca‐cola, 250 ml 11 vol% red wine and 60 ml 43 vol% whisky. Gastric potential difference decreased after intake of 250 ml ethanol 11 vol% and 60 ml ethanol 43 vol%. Intake of red wine and whisky resulted in a significant greater gastric potential difference decrease compared to similar concentrations and volumes of ethanol. The time until the potential difference had regained baseline level was longer after intake of red wine compared to coca‐cola, whisky and ethanol. Oesophageal pH decreased after intake of coca‐cola and red wine, but was unchanged after whisky. Gastric pH was unchanged after intake of all the drinks. In conclusion, the gastric potential difference reduction was not correlated to alcohol concentration. Red wine seems to affect the gastric potential difference more than coca‐cola, whisky and ethanol. The observed changes in oesophageal and gastric potential difference might be due to changes in Cl secretion and/or due to a damaging effect of the additives of the beverages.
Increased Striatal Lipid Peroxidation after Intracerebroventricular MPP+ Administration to Mice
Authors: Rojas Patricia , Rios Camilo
Published: March 2009

Abstract: Mice received different doses intracerebroventricularly of MPP+ (1‐methyl‐4‐phenylpyridinium ion), the active metabolite of MPTP (1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine), a drug which induces a Parkinson model in rodents. Two indexes of lipid peroxidation were monitored at different times after administration: 1) production of thiobarbituric acid‐reactive substances and 2) formation of lipid fluorescence products. A regional‐selective overproduction of thiobarbituric acid‐reactive substances was observed in corpus striatum and midbrain, but not in frontal cortex, cerebellum nor hippocampus. Enhancement was 70% and 198% at 30 and 60 min. in striatum and 88% at 30 min. in midbrain, when compared with respective controls injected intracerebroventricularly with saline solution. MPP+ also induced lipid fluorescence products formation enhancement in corpus striatum. This increase was dose‐dependent in the range of MPP+ doses which induced striatal dopamine depletion. Striatal LFP formation was found increased 24 hr after MPP + administration (38% vs control), indicating long‐lasting lipid peroxidation overproduction. These results suggest that lipid peroxidation might be involved in the neurotoxic effects of MPP+ in vivo.
Inhibition of Glucagon‐Stimulated Glycogenolysis by S‐Nitroso‐N‐acetylpenicillamine*
Authors: Brass Eric P. , Vetter William H.
Published: March 2009

Abstract: Rat liver is known to contain both a nitric oxide‐stimulated guanylate cyclase and a cGMP‐stimulated cAMP‐phosphodiesterase. To evaluate the possible function of this system, the effect of the nitric oxide generating compound S‐nitroso‐N‐acetylpenicillamine on glycogenolysis was evaluated in isolated rat hepatocytes. S‐nitroso‐N‐acetylpenicillamine (1.0 mM) inhibited glucagon‐stimulated glycogenolysis by 15%, but had no effect on basal rates of glycogenolysis. Inhibition of hepatocyte glycogenolysis by S‐nitroso‐N‐acetylpenicillamine was associated with accumulation of cGMP (1.5 pmol/2.0 × 106 cells/2 min.). Exogenous 8‐Br‐cGMP (1.0 mM) inhibited hepatocyte glucagon‐stimulated glycogenolysis by a magnitude similar to that observed with S‐nitroso‐N‐acetylpenicillamine. S‐nitroso‐N‐acetylpenicillamine had no effect on phenylephrine‐stimulated glycogenolysis, but inhibited 8‐bromo‐cAMP‐stimulated glycogenolysis by 15%. These observations suggest that S‐nitroso‐N‐acetylpenicillamine inhibits cAMP‐mediated stimulation of glycogenolysis at a site distal to adenylate cyclase. In summary, hepatocyte glucagon‐stimulated glycogenolysis was inhibited to a small, but significant, degree by S‐nitroso‐N‐acetylpenicillamine. This inhibition is consistent with a nitric oxide mediated stimulation of guanylate cyclase and consequent stimulation of cAMP‐phosphodiesterase activity. Nitric oxide may contribute to altered carbohydrate homeostasis under pathophysiologic conditions.
Bioactivation of 2‐Amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]‐pyridine by Liver Microsomes from Three Different Rat Strains
Authors: Dragsted L. O. , Alexander J. , Wallin H. , Frandsen H. , Vang O.
Published: March 2009

Abstract: The biotransformation of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]‐pyridine (PhIP) and the protein binding of PhIP and 2‐amino‐3‐methylimidazo[4,5‐f]quinoline (IQ) was studied using microsomes from PCB‐pretreated or untreated male rats of the strains, Wistar, Fischer and Sprague‐Dawley. The microsomal monooxygenases, P450IA1 and IA2, which are important for the biotransformation of heterocyclic amines, were quantified by immunoblots. The two metabolites detected, 2‐amino‐1‐methyl‐6‐(4′‐hydroxyphenyl)imidazo[4,5‐b]pyridine (4′OH‐PhIP) and 2‐hydroxyamino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (N2‐OH‐PhIP) were formed in similar amounts whereas no minor metabolites were found in our highly sensitive radiochemical assay. Irrespective of the rat strain used, pretreatment with PCB significantly induced both the activation and the detoxication in all three rat strains. Except for a significantly higher concentration of P450IA2 in microsomes from control and PCB induced Wistar rats, no major differences between the strains were found.
Changes in Expression of the Albumin, Fibronectin and Type I Procollagen Genes in CCl4‐Induced Liver Fibrosis: Effect of Pyridoxol L,2‐Pyrrolidon‐5 Carboxylate
Authors: Arosio B. , Santambrogio D. , Gagliano N. , Annoni G.
Published: March 2009

Abstract: The protective activity of pyridoxol L,2‐pyrrolidon‐5 carboxylate (metadoxine) was investigated in a rat model of carbon tetrachloride (CCL4)‐induced hepatic fibrosis. After 6 weeks of CCl4 treatment, the animals developed fibrosis and inflammation of the liver while those treated with CCl4 + metadoxine had less severe lesions (P<0.05). Since in liver fibroplasia there are quantitative changes of the extracellular matrix components and almost invariably a decrease in albumin synthesis, we have also investigated by Northern blot analysis the expression of the cellular fibronectin, pro‐alpha2(I)collagen and albumin genes. There were striking increases in fibronectin and pro‐alpha2(I)collagen mRNA contents in the livers of CCL4‐treated animals and these enhancements were less evident in the metadoxine‐treated rats. In contrast, albumin mRNA levels, almost identical in control and metadoxine‐treated rats, were lower in the CCl4‐treated animals. These data suggest that metadoxine might slow the development of CCl4‐mediated liver fibrosis.
Dactinomycin® Analogues as Neurokinin‐2 Receptor Antagonists
Authors: Auberson S. , Mauger A. B. , Lundberg J. M.
Published: March 2009

Abstract: Dactinomycin® has recently been shown to be a competitive neurokinin‐2 receptor antagonist in addition to its inhibiting action on DNA replication. We investigated in the isolated guinea‐pig bronchi the action of 3 Dactinomycin analogues on the contractions evoked by the selective neurokinin‐2 receptor agonist [Nle10] neurokinin A(4–10). These analogues included 4,4′‐Gly‐Dactinomycin and the single peptide lactone of dactinomycin which are inactive on DNA replication and 5,5′‐MeLeu‐Dactinomycin, which has potent antitumour activity. Independently of their known effect on DNA replication, the three analogues showed neurokinin‐2 antagonistic activity which was lower than for Dactinomycin.
Vitamin A, a Useful Biochemical Modulator Capable of Preventing Intestinal Damage during Methotrexate Treatment
Authors: Nagai Yasuharu , Horie Toshiharu , Awazu Shoji
Published: March 2009

The effects of vitamin A on methotrexate treatment of mice inoculated with L1210 leukaemia cells or sarcoma 180 cells were studied. The small intestine of tumour transplanted mice was severely damaged after methotrexate treatment. Coadministration of vitamin A with methotrexate protected the small intestine from methotrexate‐induced damage. The protective effect of vitamin A was histologically and biochemically demonstrated. Further, coadministration of vitamin A did not inhibitin vivoantitumour activity of methotrexate. Thus, biochemical modulation used to prevent methotrexate‐induced malabsorption by vitamin A coadministration will be of great use in methotrexate cancer chemotherapy.
Glucagon Produced by Recombinant DNA Technology: Repeated Dose Toxicity Studies, Intravenous Administration to CD Rats and Beagle Dogs for Four Weeks
Authors: Eistrup C. , Hjortkjæ R. K. , Pickersgill N. , Virgo D. M. , Woolley A. P. A. H.
Published: March 2009

The toxicity of glucagon produced by recombinant DNA technology (Glucagon (ge)®) was studied by daily intravenous administration to rats and dogs for 4 weeks. Pancreatic glucagon of bovine or porcine origin (Glucagon Novo®) was used as a reference control in the dogs. Glucagon (ge)® has the same sequence of the 29 animo acids as pancreatic glucagon of humans, cows, pigs, rats and dogs. The dosages were 0 (control), 0.2, 1.0 and 5.0 mg Glucagon (ge)®/kg/day in the rats, and 0 (control), 1.0 and 5.0 mg Glucagon (ge)® and 5.0 mg Glucagon (Novo)®/kg/day in the dogs. The studies complied with current EEC, US and Japanese guidelines for 4 week toxicity studies of drugs. All dose levels were well tolerated. The plasma glucose and cardiovascular responses to dosing were monitored in the dogs and found to be in agreement with well‐known effects of pancreatic glucagon. The most consistent finding in both species was an increase in liver weight. This change was without concomitant pathological deviations in the other parameters examined. There were no differences in the reaction of dogs following treatment with Glucagon (ge)® or Glucagon (Novo)®. A dose of 1 mg Glucagon (ge)®/kg/day was regarded as a clear no‐toxic‐effect‐level in both species.
Effects of Amitraz on Motor Function *
Authors: Florio J. C. , Sakate M. , Palermo‐Neto J.
Published: March 2009

The effects of amitraz, a formamidine derivative, on motor function were studied in rats. Behavioural and neurochemical studies were performed. Results show that amitraz was able: 1) to decrease locomotion and rearing frequencies of rats and to increase their immobility time in an open‐field; 2) to displace to the left the control dose‐response curve constructed to apomorphine‐induced stereotyped behavior; 3) to potentiate both pentobarbital sleeping time and amphetamine effects on open‐field behaviour of rats and 4) to increase not only the whole brain levels of noradrenaline but also the striatal levels of dopamine. In relation to control animals, the pesticide also induced 5) a decrease in the striatal levels of homovanillic acid, 6) pesticide effects on open‐field behaviour of rats were not antagonized by yohimbine administration, and 7) metoclopramide administration on amitraz pretreated rats antagonized not only amphetamine effects on open‐field behaviour, but also apomorphine‐induced stereotypy. These results are discussed in the light of the actions of amitraz on biogenic amines. It is suggested that the pesticide effects on motor function are consequences of the inhibitory effects on MAO activity, most probably through the increases produced on catecholamine levels within the central nervous system.
Pharmacokinetics and Pharmacodynamics of Pentazocine in Children
Authors: Hamunen Katri , Olkkola Klaus T. , Seppäiä Timo , Maunuksela Eeva‐Lüsa
Published: March 2009

Pharmacokinetics and ventilatory effects of a single intravenous dose of 0.5 mg/kg of pentazocine were studied in ten children aged 4 to 8 years after ophthalmic surgery. Elimination half‐life (mean ± S.D.) was 3.0×1.5 hr and clearance 21.8×5.9 ml/min./kg. The values for Vc, Vss and Vβ were 0.73×0.21, 4.0×1.2 and 5.3×2.1 1/kg, respectively. The pharmacokinetic parameters were similar to those of adults. After administration of pentazocine decrease in ventilatory rate and oxygen saturation and increase in end‐tidal carbon dioxide were relatively fast and steep. Oxygen saturation of four patients decreased below 90% and in one patient the decrease did not recover instantly and additional oxygen was given for 2 min. No patient needed assisted ventilation. Only clinically insignificant changes in heart rate and mean arterial pressure were observed. The duration of analgesia was 164 × 59 min. No serious side‐effects appeared.
ATP Leakage from ELD Cells after Exposure to Stearic, Monochlorostearic, Dichlorostearic, and Oleic Acids
Authors: Ewald Göran , Sundin Peter
Published: March 2009

The capacity of stearic, monochlorostearic, dichlorostearic and oleic acids to cause membrane damage was measured as their ability to induce leakage of adenosine triphosphate (ATP) from mammalian tumour cells in vitro. Chlorinated stearic acids, and oleic acid, caused ATP leakage at lower concentrations than normal stearic acid. The membrane disturbing properties are suggested to be a result of the different molecular geometries of the chlorinated stearic acids, and oleic acid, compared to non‐chlorinated stearic acid.
Identification of the Gastrointestinal Absorption Site for Cadmium Chloride in Vivo
Authors: Sørensen J. A. , Nielsen J. B. , Andersen O.
Published: March 2009

Most models for the study of the mechanism of intestinal absorption of Cadmium (Cd) have been using intestinal tissue in vitro or in situ. The in vivo experiments reported in this article were performed in an attempt to localize the site for gastrointestinal absorption of cadmium chloride during natural physiological conditions by oral exposure of mice to 109Cd‐labelled CdCl2. Independent of exposure via drinking water or oral administration of a single dose, Cd was primarily deposited in the most proximal duodenum. Thus the present study as well as others indicate that absorption takes place in the proximal part of the intestine. Absorbed Cd is initially transported to the liver and deposited before being redistributed and accumulated in the kidneys. In this experimental model, dietary tetraethylthiuram disulfide exposure was shown to change the intestinal labelling profile and increase the whole‐body retention as well as the intestinal deposition of Cd.
Evidence for Lysosomotropism of Memantine in Cultured Human Cells: Cellular Kinetics and Effects of Memantine on Phospholipid Content and Composition, Membrane Fluidity and β‐Adrenergic Transmission
Authors: Honegger U. E. , Quack G. , Wiesmann U. N.
Published: March 2009

Memantine, an amantadine derivative, is therapeutically used for the treatment of various neurological and psychiatric disorders such as Parkinson's disease, spasticity, and dementia. Pharmacokinetics of memantine and its effects on phospholipid content and composition, on membrane properties and functions such as fluidity and β‐adrenergic transmission were studied in cultured human fibroblasts and macrophages. The kinetic behaviour of memantine was characteristic for a lysosomotropic drug. Fibroblasts exposed to14C‐memantine in the μM range accumulated the drug up to 200 fold above initial medium concentrations. Lysosomal drug storage was proven by indirect evidence and by analyses of subcellular fractions. Repetitive exposure to memantine resulted in a cumulative uptake. While memantine uptake after single exposure was fully reversible, the rate and extent of release of chronically accumulated drug was reduced but could be enhanced by the addition of unlabelled memantine or ammonium chloride to the medium. Chronic, but not single, exposure to memantine above 10 μM resulted in a concentration dependent phospholipid accumulation and in a shift in the phospholipid composition. There was an overproportionate increase in phosphatidylinositol at the expense of phosphatidylserine and sphingomyelin. Chronic exposure of cultured cells to memantine increased fluidity in the superficial layers of the plasma membrane and reduced the isoproterenol‐stimulated cAMP‐response without affecting β‐adrenoceptor density. All these findings were compatible with the kinetic behaviour and the effectiveness expected of a weak lysosomotropic drug.
Lipid Peroxidation and Antioxidant Defense Enzymes in Various Regions of Adult Rat Brain after Co‐Exposure to Cadmium and Ethanol
Authors: Pal Raman , Nath Ravindra , Gill Kiran Dip
Published: March 2009

Effect of cadmium (1 mg/kg body weight) and ethanol (2 g/kg body weight) exposure, alone as well as in combination, on essential trace metal homeostasis, lipid peroxidation and antioxidant defense enzymes in various regions of the adult rat brain was investigated. It was observed that cadmium when administered alongwith ethanol accumulated significantly in corpus striatum (3.5 fold) and cerebral cortex (3.0 fold) compared to the cadmium treated group. The ethanol induced accumulation of cadmium led to significant depletion in the levels of essential trace metals like zinc and copper in these regions of the brain. Further, cadmium or ethanol alone did not show any significant effect on lipid peroxidation and antioxidant defense enzymes in any of the regions of the adult brain but when given in combination, caused a significant increase in lipid peroxidation and markedly decreased the activities of antioxidant defense enzymes like glutathione peroxidase, superoxide dismutase and catalase particularly in corpus striatum and cerebral cortex. Structural alterations produced by increased lipid peroxidation after cadmium and ethanol co‐exposure may have profound effect on the activities of membrane bound enzymes and hence may lead to functional impairment. The results of the present study imply that ethanol renders the adult brain more susceptible to the neurotoxic effects of cadmium. Corpus striatum and cerebral cortex are more vulnerable to the toxic effects of cadmium under the influence of ethanol than other regions of the brain.
Localization of Thermogenesis Induced by Single Infusion of Ephedrine in Dog
Authors: Madsen J. , Billow J. , Larsen O.G. , Hartkopp A. , Nielsen N. E. , Astrup A. , Christensen Niels Juel
Published: March 2009

The localization of the thermogenic effect of ephedrine (1 mg · kg‐1 infused intravenously over 10 min.) was studied in 6 fasted dogs anaesthetized with etorfin‐acepromazin‐N2O. Three experiments were performed in each animal to determine the effect of ephedrine on a) splanchnic oxygen uptake, b) lower leg oxygen uptake and c) the work of the heart. In all experiments whole body oxygen uptake was monitored. Following ephedrine administration the following significant changes were seen as whole body oxygen uptake increased 16%, and splanchnic and lower leg oxygen uptakes increased respectively from 38.4 to 42.3 and from 7.3 to 12.1% of the whole body control oxygen uptake. The pressure‐volume work of the heart more than doubled. Significant changes were also seen in mean arterial blood pressure, pulse rate, cardiac output, splanchnic blood flow, and haematocrit and haemoglobin concentration. Plasma glycerol and free fatty acid concentrations increased after ephedrine, and the effects were not elicited by circulating catecholamines.
Inhibition of Hepatic Xenobiotic Metabolism and of Glutathione‐Dependent Enzyme Activities by Zinc Ethylene‐Bis‐Dithiocarbamate in the Rabbit *
Authors: Nebbia C. , Dacasto M. , Soffietti M. Gennaro , Rasero R. , Principato G. B. , Di Simplicio P.
Published: March 2009

Effects of either a single (300 mg/kg) or a subchronic (0.3 and 0.6% for 70 days) oral administration of a dithiocarbamate fungicide (zinc ethylene‐bis‐dithiocarbamate, zineb) on hepatic drug metabolism and on the activity of several glutathione‐dependent enzymes were investigated in male New Zealand White rabbits. While a pronounced reduction in the rate of oxidative biotransformations occurred after either single or repeated exposure, both cytochrome P450 and total haem content were lowered following acute challenge to zineb. None of the experimental protocols affected microsomal carboxylesterase but induced a marked increase in glutathione content and none of the examined glutathione‐dependent enzymes was altered by the single administration of zineb, whereas the subchronically exposed rabbits showed a fall in the activites of both total glutathione S‐transferase and selenium‐independent glutathione peroxidase. In the 0.6% treated animals, a decrease in class μ glutathione S‐transferase and glyoxalase I, and an increase in thiol‐transferase activities were also recorded. It is concluded that (1) zineb is able to selectively impair oxidative drug metabolism with possible different mechanism(s) according to the duration of the exposure, (2) only the subchronic treatment affects glutathione‐dependent enzymes, (3) the decrease in glutathione S‐transferase activity would seem to be ascribed to a direct interaction with the fungicide.
In vitro Evaluation of Acute Effects of Mitoxantrone (Novantrone®) in Rat and Guinea Pig Atria
Authors: Viglione P. N. , Praprotnik A. , Pinto J. E. B.
Published: March 2009

Abstract:Since guinea pig and rat atria have been used as models to study acute anthracycline‐induced cardiotoxicity, experiments were carried out in these preparations to evaluate possible acute cardiac effects mediated by mitoxantrone (MTX). After a latency period of approximately 90 min, MTX (10‐5—10‐4M) promoted a concentration‐related and time‐dependent decrease of spontaneous rate in guinea pig atria. A similar but less intense effect after a longer latency interval was observed in rat atria. In this preparation, MTX (10‐5—10‐4M) incubated up to 150 min., induced a gradual competitive β‐adrenergic blocking effect on the positive chronotropic action of isoproterenol. This was characterized by a progressive decline of pD2values without altering Emax. A similar and stronger effect was found in isolated guinea pig atria incubated under same conditions with MTX, except that 10‐4M exposed for 150 min. was able to depress the Emaxto isoproterenol by 21.2%. In addition, MTX (10‐4M) in this model promoted a non‐competitive antagonistic effect on the chonotropic action of histamine. These data are compatible with the idea that MTX could induce cardiac acute effects qualitatively similar to but of lower potency than those produced by doxorubicin in these two models. In addition, guinea pig atria seemed to display higher sensitivity to MTX compared to rat atrial preparations.
Comparison of Calcipotriol with Selected Metabolites and Analogues of Vitamin D3: Effects on Cell Growth Regulation in Vitro and Calcium Metabolism in Vivo
Authors: Binderup Lise
Published: March 2009

Abstract: Calcipotriol is a novel vitamin D3 analogue developed for topical treatment of psoriasis. Calcipotriol is believed to act via regulation of cell proliferation and differentiation. In this respect calcipotriol is as potent as 1α,25(OH)2D3, the physiologically active form of vitamin D3, but its calcaemic activity in vivo is 100 to 200 times lower. In the present investigation, the effects of calcipotriol on cell growth regulation in vitro and on calcium metabolism in vivo were compared to those exerted by a number of metabolites and analogues of vitamin D3. Besides 1α,25(OH)2D3, these included the two physiologically occurring metabolites 25(OH)D3 and 24,25(OH)2D3, and the two synthetic analogues 1α(OH)D3 and 1α,24(OH)2D3. 25(OH)D3 and 24,25(OH)2D3 were shown to be inactive both in vitro and in vivo. 1α(OH)D3 was found to have a low biological activity in vitro, but was highly calcaemic in vivo after biotransformation to 1α,25(OH)2D3. Calcipotriol, 1α,24(OH)2D3 and 1α,25(OH)2D3 were all three potent regulators of cell proliferation and differentiation in vitro. In vivo, only calcipotriol showed a greatly reduced calcaemic activity after both oral and intravenous administration. It is concluded that calcipotriol, with a reduced risk of inducing calcaemic side‐effects upon absorption from the skin, possesses a favourable therapeutic profile for topical treatment of hyperproliferative diseases.
New Evidence for a Loss of Serotonergic Nerve Terminals in Rats Treated with d,l‐Fenfluramine
Authors: Westphalen Robert I. , Dodd Peter R.
Published: March 2009

Abstract:Fenfluramine has been classified as a neurotoxin because animals treated with this anorectic lose 5‐HT uptake sites located on serotonergic nerve terminals. However, there are two possible bases for this finding:eitheruptake sites are lost because the terminals themselves have been destroyed (neurotoxicity);oruptake sites are lost from otherwise intact terminals. To distinguish between these possibilities, we established an animal model in which male Wistar rats were injected (intraperitoneally) with an irreversible 5‐HT uptake site antagonist (EEDQ). Since their 5‐HT sites were inhibited (blocked) non‐competitively, by this agent, such animals had effectively lost 5‐HT uptake sites from intact serotonergic terminals. Synaptosomes prepared from such animals showed the predicted reduction in theBmaxof [3H]paroxetine binding to the 5‐HT uptake site, and a reduction in the Vmaxof [14C]5‐HT uptake. However, they showed no significant reduction in maximal [14C]5‐HT loading (α) compared with synaptosome from sham‐injected controls. In contrast, fenfluramine‐treated animals showed reduced [3H]paroxetine binding, reduced maximal [14C]5‐HT uptake and significantly (P<0.02) reduced synaptosomal [14C]5‐HT loading. Therefore, the results suggest that fenfluramine does indeed cause the destruction of serotonergic nerve terminals.
Effect of Epomediol on Taurocholate Uptake in Hepatocytes Isolated from Normal Rats or Rats with Ethinyloestradiol‐Induced Cholestasis
Authors: Barone M. , Azzarone A. , Angelini A. , Zamparella M. , Dell'Aquila P. , Francavilla A.
Published: March 2009

Abstract: In this study the effect of epomediol (1,3,3‐trimethyl‐2‐oxabicyclo 2.2.2 ocatan‐6,7‐endo, endo‐diol) (Clesidren®) on rat hepatocyte bile acid transport was evaluated using [3H]‐taurocholate as a probe, in order to clarify the mechanism of action of this drug. To this purpose, primary cultures were prepared with hepatocytes obtained from normal rats (Group I), and rats receiving a 4‐day treatment with either epomediol (100 mg/kg) (Group II), or ethinyloestradiol (5 mg/kg) (Group III), or ethinyloestradiol plus epomediol (5 mg and 100 mg/kg respectively) (Group IV) or vehicle DMSO 50 μl/kg) (Group V). All hepatocytes were isolated 10 days after the end of treatment. Hepatocyte [3H]‐taurocholate uptake was evaluated in vitro after 48 hr of incubation in the presence or absence of epomediol. In both cases no difference was found when evaluating the uptake of hepatocytes from Group I, II and V. In the absence of epomediol [3H]‐taurocholate uptake in hepatocytes from rats of Group IV was significantly higher than that observed in hepatocytes from rats of Group III. On the other hand, the presence of epomediol did not influence [3H]‐taurocholate uptake in hepatocytes from rats of Group III, which remained significantly lower compared to that of control hepatocytes (Group V). The protective effect obtained when administering epomediol simultaneoulsy with ethinyloestradiol (Group IV) was not due to its ability to compete with ethynyloestradiol for the binding to oestrogen receptors. Our results indicate that epomediol is able to restore a normal hepatocyte bile acid uptake when given in vivo simultaneously with ethinyloestradiol but does not influence bile acid transport in cultured hepatocytes. Further studies are required to better define the choleretic activity of this drug.
Immunohistochemical Localization of α and φ Class Glutathione Transferases in Normal Human Tissues
Authors: Sundberg Anders G. M. , Nilsson Robert , Appelkvist Eeva‐Liisa , Dallner Gustav
Published: March 2009

Abstract: The distribution of α and φ class glutathione transferases in autopsy and biopsy samples of normal human tissues was investigated by immunohistochemistry. The class α glutathione transferases exhibited restricted distribution. Intensive staining was visible in all hepatocytes, in kidney proximal tubular cells, in the zona reticularis of adrenal cortex and in Leydig cells of testis. Staining of lesser intensity could also be observed in the gastrointestinal epithelium, exocrine pancreas and some bile and pancreas ducts. In colon and gall bladder only nuclei were stained, but in the other tissues both nuclei and cytoplasm contained α class glutathione transferases. Glutathione transferase φ exhibited a more general distribution and could be observed in epithelia of the respiratory, gastrointestinal and urinary tracts, in all endocrine cells investigated, and also in the exocrine glands of prostate, in smooth muscle, adipocytes, blood vessel endothelium and placenta. It was also visible in the Schwann cells of peripheral nerves and in the choroid plexus. In gall bladder and colon only nuclei were stained, while in the intrahepatic bile ducts only cytoplasm was stained. All other positive cells exhibited glutathione transferase φ in both nuclei and cytoplasm.
Mechanistic Modelling and Risk Assessment
Authors: Portier Christopher J.
Published: March 2009

Abstract: Risk Assessment in the United States has been rapidly changing over the last few years. The historical methods and endpoints by which risk estimates were derived are gradually being replaced by newer methods and a broader spectrum of endpoints. For carcinogenic risk assessment, there is movement from the routinely used “linearized multistage model” for low dose risk estimation to methodology which is more deeply rooted in carcinogenic mechanisms and which allows the incorporation of additional data into the estimation of risks in a direct, quantitative fashion. There is also a determined effort under way to develop methods for assessing risks from exposure based on other endpoints such as effects on the immune system and the reproductive system. This paper briefly discusses some of the statistical and mathematical issues which will play important roles in determining the utility and precision of these new methods for estimating risks from environmental exposures.
Occurrence of Carcinogens in the External Environment: Epidemiological Investigations
Authors: Møller Henrik
Published: March 2009

Abstract: The variation in cancer incidence between European populations indicates that at least 50% of the cancer incidence in Denmark may be attributable to environmental factors, including factors related to living conditions and lifestyle, and, hence, in principle are avoidable. Based on data from epidemiological studies of cancer causes, it is estimated that 30‐40% of the total cancer burden in Denmark could be prevented by application of already available knowledge. Epidemiological studies of cancer occurrence in relation to arsenic in drinking‐water, chlorination of drinking‐water, nitrates in drinking‐water and ambient air pollution are briefly reviewed. Although the causal associations between these factors and cancer in humans are hypothetical and unproven, the available data allow a rough calculation of the maximum proportion of cancer cases which possibly can be caused by these factors. At most, a few percent of the total cancer incidence is attributable to these external environmental factors.
Risk Assessment for People Exposed from Different Environments
Authors: Poulsen Emil
Published: March 2009

Abstract: After the identification of the hazardous intrinsic properties of a carcinogen an attempt is made to estimate, if possible, the potency of the carcinogenic effect. For the evaluation it is, furthermore, of interest to know the genotoxic properties of the chemical. The next step would be to try to estimate the potential exposure for people in different environments. This could be intake from use of it as an additive in food or occurrence as a contaminant in food, drinking water, soil or air. The air exposure might come from contaminants in the working environment, in‐door air or ambient air.

The outcome of the hazard and exposure assessments would not be the only factors in a risk assessment or suggested limit values. Other factors might be the political‐administrative background coming from different legal systems, even in the same country, which might apply different safety ambitions. This might result in the application of different risk levels (1:1 million, 1:10 million) or different safety factors, if that approach is used for non‐genotoxic animal carcinogens.
Cancer and Ionizing Radiation
Authors: Ulbak Kaare
Published: March 2009

Abstract: The carcinogenic effects of ionizing radiation are well documented at high doses and high dose rates. The Danish population has always been exposed to ionizing radiation from natural sources. In this century exposures from man‐made sources especially in the medical field have added to the overall exposure of the population. Excluding medical exposures and exposures in the working environment the exposures of an individual member of the Danish population are essentially coming from natural sources especially from radon in dwellings. On average these sources give an annual effective dose equivalent of 3 mSv.

A risk assessment using the latest information on the carcinogenic effects of ionizing radiation indicate that these radiation sources could give rise to 300 lung cancer deaths (radon) and 250 fatal cancers (other sources) each year in Denmark.
Cancer and UV‐Radiation
Authors: Østerlind Anne
Published: March 2009

Abstract: Solar radiation is a well documented risk factor in melanoma and non melanocytic skin cancer (i.e. basal cell and squamous cell carcinoma). It has been suspected to play a role also for lip cancer and for eye melanoma. Primary prevention should include advises to the public about sensible sun exposure. Results of such efforts will be apparent only in a long term perspective.
Carcinogenic Chemicals in the Occupational Environment
Authors: Anttila Ahti , Sallmén Markku , Hemminki Kari
Published: March 2009

A survey of occupational carcinogens by the Institute of Occupational Health, Finland shows that more than 100 000 workers are exposed to carcinogenic substances. The most common exposures are silica, wood dust, tobacco smoke and lead compounds. Based on biological monitoring of workers over the years it appears that overall lead exposure has decreased but exposure to styrene, trichloroethylene and tetrachloroethylene has decreased only slightly or remained constant. The biological monitoring data are based on samples sent by the workplaces on their initiative presenting no scientifically selected sampling. Thus due caution is needed in the interpretation of the trends.