bluuebunny/crossref_metadata_2025 huggingface dataset:
Nitrofurantoin‐Induced Hepatic and Pulmonary Biochemical Changes in Mice Fed Different Vitamin E Doses
Authors: Adam Aishah , Marzuki Alini , Ngah Win Zurinah Wan , Top Gapor Md.
Published: March 2009

Abstract:The hepatic and pulmonary effects of nitrofurantoin (40 mg/kg, intraperitoneally) were determined at 4 and 24 hr following its administration in mice fed for 10 weeks with a vitamin E sufficient, deficient or enriched diet. Liver glutathione (GSH) was reduced by nitrofurantoin at 4 hr but was unchanged 20 hr later. Nitrofurantoin did not affect liver glutathione peroxidase, glutathione reductase or superoxide dismutase activities. Liver catalase activities were decreased by nitrofurantoin at 4 hr. Lung GSH levels were increased whilst glutathione peroxidase activity was decreased at 4 and 24 hr. Lung glutathione reductase activity was reduced in certain groups. Nitrofurantoin did not affect lung superoxide dismutase, but catalase was decreased at 24 hr. Liver malondialdehyde levels were increased by nitrofurantoin in the vitamin E deficient group whilst lung malondialdehyde levels remained unchanged. Both liver and lung malondialdehyde levels were unaffected by vitamin E supplementation when compared to the vitamin E‐sufficient group. These results suggest that nitrofurantoin (40 mg/kg) was deleterious to the liver and lung. Nitrofurantoin‐induced lipid peroxidation was seen in vitamin E deficiency but an increase in dietary vitamin E content did not provide additional protection compared to the recommended daily allowance. The antioxidant acitivities of α‐tocopherol and γ‐enriched tocotrienol were similar.
Effects of Benzopsoralen Derivatives on HL60 and HeLa Cells
Authors: Conconi Maria Teresa , Valenti Fabio , Montesi Francesco , Bassani Valeria , Angeli Sergio De , Parnigotto Pier P.
Published: March 2009

Abstract: The effect of 4‐hydroxymethyl‐6, 7, 8, 9‐tetrahydro‐2H‐benzofuro‐[3,2‐g]‐1‐benzopiran‐2‐one (compound 1) and 4‐hydroxymethyl‐2H‐benzofuro‐[3,2g]‐1‐benzopiran‐2‐one (compound 2), two new benzopsoralen derivatives, was tested on HL60 and HeLa cell lines in the dark and by UVA irradiation; 8‐methoxypsoralen was used as a reference compound. The action of the compounds was evaluated by means of the neutral red uptake assay, by means of ultrastructure, morphometry and interaction with human erythrocytes membrane. In both HL60 and HeLa cell lines benzopsoralen derivatives showed more antiproliferative activity after UVA irradiation, however less than 8‐methoxypsoralen. Compound 1 was more effective than compound 2 both in the dark and after UVA irradiation. The ultrastructure showed a morphological rank damage caused by these compounds: compound 2 induced slight modifications in the cytoplasm organization, compound 1 induced some vacuolizations and 8‐methoxypsoralen generated plenty of vacuoles and an empty space around the nucleus. Morphometrical data in HL60 cells turned out to be in accordance with the different action mechanisms existing between 8‐methoxypsoralen and the two benzopsoralen derivatives; in HeLa cells we noted an increase in the nuclear area induced by all the three compounds. Only compound 1 caused the formation of echinocytes both in the dark and after UVA irradiation, suggesting the involvement of a mechanism not strictly related to DNA interaction and singlet oxygen production.
The Use of β2‐Adrenoceptor Agonists in the Treatment of Bronchial Asthma
Authors: Svedmyr Nils , Löfdahl Claes‐Göran
Published: March 2009

Abstract:All guidelines recommend short‐acting inhaled β2‐adrenoceptor agonists as the first‐line drugs in acute asthma attacks and inhaled corticosteroids as the drugs of choice when regular daily treatment is needed. Short‐acting inhaled β2‐adrenoceptor agonists are not effective in reducing nocturnal awakenings because of their short duration of action. In addition there has been an intense debate about the regular use of these drugs. This debate is reviewed. They shold only be used on "as needed basis". The Swedish guidelines for the treatment of asthma were the first to recommend the new long‐acting inhaled β2‐adrenoceptor agonists at relatively early stage of the illness (800 μg daily of inhaled corticosteroids). Two recently completed large multicentre studies with salmeterol in asthmatics support this opinion. Both studies showed a better asthma control with a combination of a low inhaled steroid dose and salmeterol compared to a doubling of the steroid dose. In most asthmatic patients, still symptomatic on inhaled steroids doses 400 to 800 μg daily, a test of the addition of inhaled salmeterol is recommended. The steroid dose can be kept low and safe. However, asthmatic patients with either frequent or severe exacerbations should primarily have their steroid dose increased.
Pharmacological Treatment of Central Nervous System Trauma
Authors: Faden Alan I.
Published: March 2009

Abstract:Traumatic injuries to the brain or spinal cord cause tissue damage, in part by initiating reactive biochemical changes. Pharmacological approaches aim to modify this delayed injury response by blocking one or more components of the reactive biochemical/metabolic cascade. This minireview summarizes both historical and recent developments in experimental and clinical treatment of CNS trauma. Potential treatments include: corticosteroids; antioxidants or free radical scavengers; drugs that modify arachidonic acid metabolism, platelet‐activating factor antagonists; gangliosides; modulators of monoamine actions; opioid receptor antagonists; thyrotropin‐releasing hormone and thyrotropin‐releasing hormone analogues; glutamate receptor antagonists; calcium channel blockers; agents that modify the inflammatory/ immune response; and trophic factors. Understanding the mechanisms of action for these compounds can permit rational drug development/application, delineation of the therapeutic window, and laying of the ground‐work for evaluating potential synergistic effects of combination treatment strategies.
BB‐882 is a Potent Antagonist of the Haemodynamic Changes Induced by Platelet‐Activating Factor in Pigs
Authors: Abu‐Zidan Fikri M. , Walther Sten , Lennquist Sten
Published: March 2009

Abstract:The effects of bolus doses (0.2‐2 μg) of platelet‐activating factor (PAF) on systemic and pulmonary arterial pressures were tested in five juvenile pigs, and were demonstrated to have a biphasic effect. There was an initial drop in the mean systemic arterial pressure within seconds, followed by an increase within 1‐2 min., whereas mean pulmonary arterial pressure only rose. The response was dose‐related and did not include tachyphylaxis. The pressures returned to baseline within 10 min. After confirming these results a novel specific PAF receptor antagonist (BB‐882) was given as a 1 mg/kg bolus followed by a continous infusion of 2 mg/kg/hr, and a third dose response curve was repeated with ten‐fold higher PAF doses (2‐20 μg). BB‐882 effectively counteracted these effects. Six pigs were given a continous infusion of BB‐882 33 mg/kg/hr for 5 hr and were compared with another group of five pigs given vehicle only. In this high dose BB‐882 did not affect the intravascular pressures. These results indicate that BB‐882 is a potent PAF receptor antagonist in juvenile pigs.
Demonstration of Benzo(a)pyrene‐Induced DNA Damage in Mice by Alkaline Single Cell Gel Electrophoresis: Evidence for Strand Breaks in Liver but Not in Lymphocytes and Bone Marrow
Authors: Vaghef Hamid , Wisén Anna‐Carin , Hellman Björn
Published: March 2009

Abstract:Alkaline single cell gel electrophoresis (also known as the‘comet assay') was used to measure DNA strand breaks and alkali‐labile sites in peripheral lymphocytes, bone marrow and liver cells of C57BL/6 mice orally exposed to benzo(a)pyrene. Although this polycyclic aromatic hydrocarbon is a well‐known genotoxic agent, little is known about to what extent it actually induces DNA strand breaks in peripheral lymphocytes and other tissues afterin vivoexposure. Significant and dose‐related damage was observed in liver cells after three days of exposure (lowest observed effect level being 3×100 mg benzo(a)pyrene/kg b.wt.). No such damage could be observed in the lymphocytes and bone marrow cells even after administration of 3×150 mg benzo(a)pyrene/kg b.wt. The reference substance cyclophosphamide produced pronounced DNA damage in lymphocytes and bone marrow cells already in a single dose of 100 mg/kg b.wt. The present mouse study questions the usability of DNA strand breaks in peripheral lymphocytes as an indicator of benzo(a)pyrene‐induced genotoxicity.
Characteristics of Contractile 5‐HT Receptors in Isolated Human Omental Arteries: Presence of 5‐HT1and 5‐HT2Receptors
Authors: Wallerstedt Susanna M. , Törnebrandt Kenneth , Bodelsson Mikael
Published: March 2009

Abstract:5‐Hydroxytryptamine (5‐HT) has a variety of biological effects, e.g. it induces and modulates vascular smooth muscle activity. The effects are mainly mediated via a heterogeneous group of 5‐HT receptor subtypes. In order to elucidate the 5‐HT receptor mechanisms in the human splanchnic circulation,in vitrostudies were carried out on omental arteries obtained from patients undergoing abdominal surgery. Four 5‐HT receptor agonists with different selectivity all induced concentration‐dependent contraction (potency and order of potency indicated): 5‐HT (non‐selective; 6.12 ± 0.14)=sumatriptan (5‐HT1; 6.32±0.07)>α‐methyl‐5‐HT (5‐HT2; 5.41 ± 0.05)>2‐methyl‐5‐HT (5‐HT3; ≤ 4.46±0.05). The 5‐HT1/5‐HT2receptor antagonist methiothepin antagonised the contraction induced by 5‐HT, sumatriptan, a‐methyl‐5‐HT and 2‐methyl‐5‐HT The 5‐HT2receptor antagonist ketanserin antagonised the contraction induced by 5‐HT, α‐methyl‐5‐HT and 2‐methyl‐5‐HT. The 5‐HT3receptor antagonist tropisetron did not antagonise the contraction elicited by 2‐methyl‐5‐HT. The results suggest that 5‐HT‐induced contraction in human omental arteries involves both 5‐HT1and 5‐HT2, but maybe not 5‐HT3‐receptors.
Biochemical Characterization of the Effects of the Benzodiazepine, Midazolam, on Mitochondrial Electron Transfer
Authors: Colleoni Mariapia , Costa Barbara , Gori Enzo , Santagostino Angela
Published: March 2009

Abstract: Midazolam, a water soluble benzodiazepine used as a preanaesthetic and hypnotic drug, showed a concentration‐related (0.1‐0.75 mM) depressant effect on both Adenosine 5′‐diphosphate (ADP)‐induced oxygen consumption and oxidative phosphorylation of rat liver mitochondria if the substrate was oxidized at different steps in the oxidation chain, but not when the substrate was ascorbate plus tetramethyl‐p‐phenylenediamine (complex IV). Furthermore, midazolam did not affect citrate synthase activity, but inhibited the 2,4 dinitrophenol (DNP)‐uncoupled mitochondrial respiration. This result shows that midazolam primarily acts as a mitochondrial electron transport inhibitor. This inhibition is mainly due to the fact that midazolam decreases NADH ubiquinone reductase (complex I) and ubiquinol cytochrome c reductase (complex III) activities, but it also inhibits complex II activity. Spectrophotometric measurements of redox states of rat skeletal muscle mitochondria cytochromes show a decrease in the reduction of aa3 and c+c1 cytochromes in the presence of the benzodiazepine. Midazolam significantly decreased the reduced ubiquinone/total ubiquinone ratio (evaluated by means of HPLC and electrochemical detection) in rat liver mitochondria in both P‐hydroxybutyrate and succinate. Ubisemiquinone may be the redox component affected by midazolam, whether or not bound to the iron‐sulfur proteins present in all three mitochondrial complexes. These effects of midazolam, not necessarily related to the preanaesthetic and hypnotic action are probably mediated via mitochondrial benzodiazepine receptors.
Exposure to High Environmental Temperature in the Sauna Does not Change Plasma Indocyanine Green (ICG) Clearance in Healthy Subjects
Authors: Vanakoski Jyrki , Idänpään‐Heikkilä Juliana J. , Seppälä Timo
Published: March 2009

Abstract:Indocyanine green (ICG) was given intravenously (0.5 mg kg‐1) to seven healthy male volunteers in random order during a control session and a session in the sauna bath. The sauna bathing session consisted of three 10 min. stays in the sauna (temperature 85‐95°, relative humidity 25‐30%), separated by two 5‐min. periods of resting at 22°. Blood samples were taken for 60 min. in order to calculate ICG plasma clearance (CI), volume of distribution (Vss) and elimination half‐life (t1/2β). The mean±S.E.M. values of ICG plasma clearance, Vssandt1/2βfor the control session and the sauna bathing session were 0.47±0.08 1 min.‐1versus 0.39±0.04 1 min.‐1, 2.4±0.4 1 versus 2.3±0.2 1 and 3.9±0.3 min. versus 4.4±0.3 min., respectively. No statistically significant differences in the CI,t1/2βor Vssof ICG were detected between the control and sauna bathing sessions. The results suggest that short‐term exposure to high ambient temperatures during sauna bathing does not affect hepatic blood flow. Consequently, short‐term hyperthermia and associated changes in hepatic blood flow are assumed to have little, if any, effect on the hepatic clearance of drugs.
Increase in Brain Nitric Oxide Synthase Activity in Daunorubicin‐treated Rats
Authors: Joshi P. , Vig P. J. S. , Veerisetty V. , Cameron J. A. , Sekhon B. S. , Desaiah D.
Published: March 2009

Abstract:Anthracyclines such as daunorubicin are very effective anticancer agents. These drugs are known to cause side effects including cardiotoxicity. Anthracyclines are neurotoxic to laboratory animals. Nitric oxide is a novel and very important chemical messenger in the brain. However, at higher levels, nitric oxide causes well defined neurotoxicity. Therefore, we determined nitric oxide synthase activity in rat brain after daunorubicin treatment in an effort to explain the neurotoxicity produced by anthracyclines. Male Sprague‐Dawley rats were treated with different subcutaneous doses of daunorubicin (0.1‐4.0 mg/kg/week for five weeks) while control animals were injected with phosphate buffered saline. There was a significant increase (80%) of nitric oxide synthase activity in daunorubicin‐treated animals as compared to controls. This activity was inhibited by N‐monomethyl‐L‐arginine (NMMA), nitroarginine, N‐6‐aminohexyl‐5‐chloro‐l‐napthalene sulfonamide (W‐7), a calmodulin antagonist, suggesting that the nitric oxide synthase activity is calmodulin dependent. Further, ourin vitrostudies demonstrated that daunorubicin interacted with calmodulin as measured by N‐phenyl‐1‐napthylamine (NPN) fluorescence. These results indicate that daunorubicin increases nitric oxide synthase activity in rat brain which may increase the levels of nitric oxide. The increased levels of nitric oxide may cause neurotoxicity. Our results further indicate that daunorubicin interacts with calmodulin and enhances nitric oxide synthase activity which is dependent on calmodulin.
The Effect of a‐Trinositol on Cholera Toxin‐Induced Hypersecretion and Morphological Changes in Pig Jejunum
Authors: Hansen Mark Berner , Tindholdt Tyge Tind , Elbrend Vibekc Sødring , Makinde Martin , Cassuto Jean , Beubler Eckhard , Westerberg Eva J. , Skadhaugc Erik
Published: March 2009

Abstract:α‐Trinositol (D‐myo‐inositol 1,2,6‐trisphosphatc, PP56) is a novel antiinflammatory drug. This study elucidates the effect of intravenous α‐trinositol on basal and acute fluid transport and morphological changes following cholera toxin administration in pig jejunumin vivo. Using isolated jejunal tied‐off loops, the fluid hypersecretory (accumulation) effect of different doses of cholera toxin was studied in pigs treated intravenously with saline added different doses (0,4, 8, 16 and 32 mg×kg‐1×hr‐1) of α‐trinositol. Levels of α‐trinositol, as well as stereomicroscopical, light microscopical and scanning electron microscopical morphological studies were performed. Cholera toxin evoked a dose‐dependent fluid hypersecretion. Treatment with α‐trinositol caused a dose‐dependent inhibition of the cholera toxin‐induced fluid hypersecretion and did not affect basal fluid absorption. The 16 mg×kg‐1xhr‐1α‐trinositol dose gave a maximal inhibition of 36%. Morphological studies showed only minor changes following 6 hr of exposure to 20 μg×loop‐1cholera toxin. These changes consisted of dilation of the villus capillaries, an increase of apical membrane blebbing and a reduction of the intercellular space. Treatment with 16 mg×kg‐1+hr‐1a‐trinositol alone did not induce any morphological changes, and did not alter the morphological changes induced by cholera toxin, which caused fluid hypersecretion and only minor acute morphological changes. In conclusion, a‐trinositol treatment reduced cholera toxin‐induced fluid hypersecretion without altering basal fluid absorption, basal morphology, or cholera toxin‐induced morphological changes in pig jejunumin vivo.
Morphine Withdrawal Alters Anterior Pituitary Hormone Secretion, Brain Endopeptidase Activity and Brain Monoamine Metabolism in the Rat
Authors: Idänpään‐Heikkilä Juliana J. , Rauhala Pekka , Tuominen Raimo K. , Tuomainen Päivi , Zolotov Nikolai , Männistö Pekka T.
Published: March 2009

Abstract:Rats were made tolerant to morphine by a 5‐day regimen with increasing doses. The time course of changes in serum anterior pituitary hormone levels, brain endo‐ and exopeptidase activity, levels of brain biogenic amines and body weight were studied during abrupt morphine withdrawal. Cold stimulated secretion of thyrotropin and the secretion of growth hormone were both decreased whereas that of prolactin was increased. In the hypothalamus both prolyl endopeptidase and dipeptidyl peptidase IV activities were concomitantly increased. The hypothalamic 5 hydroxyindole acetic acid levels were also increased. Changes in hormone secretion, peptidase activity and monoamine turnover had returned to baseline levels by 92 hr. Our results indicate that morphine withdrawal and the associated stress produce alterations in anterior pituitary thyrotropin and growth hormone secretion. Concomitant increases in hypothalamic prolyl endopeptidase and dipeptidyl peptidase activities may contribute to these changes.
Neuroendocrine Effects of Dexmedetomidine: Evidence of Cross‐Tolerance Between a μ‐Opioid Agonist and an α2‐Adrenoceptor Agonist in Growth Hormone Secretion of the Male Rat
Authors: Idänpään‐Heikkilä Juhana J. , Rauhala Pekka , Männistö Pekka T.
Published: March 2009

Abstract:The role of α2‐adrenergic receptors (adrenoceptors) in the secretion of growth hormone, prolactin and thyrotropin was studied using highly selective agonists and antagonists of the α2‐adrenoceptor. The interplay between opiates and α2‐adrenergic drugs in the acute secretion of growth hormone and prolactin, as well as the possible cross‐tolerance between morphine (μ‐opioid receptor agonist) and dexmedetomidine (α2‐adrenoceptor agonist) in growth hormone secretion were also evaluated. Dexmedetomidine dose‐dependently increased plasma growth hormone and prolactin levels and decreased thyrotropin levels. The enhanced secretion of both growth hormone and prolactin was antagonized by atipamezole (an α2‐adrenoceptor antagonist) but not by prazosin (an α1‐adrenoceptor antagonist). Morphine (5 mg/kg)‐induced stimulation of growth hormone secretion was antagonized by both naloxone (u‐opioid antagonist) and atipamezole. Naloxone, but not atipamezole, antagonized the morphine‐induced increase in prolactin secretion. Dexmedetomidine increased growth hormone secretion in the saline pretreated rats, but did not do so in the morphine‐tolerant rats. The stimulation of α2‐adrenoceptor enhances secretion of both growth hormone and prolactin. The adrenergic regulation of thyrotropin secretion still remains unclear. Evidently, adrenergic mechanisms are involved in the morphine‐induced stimulation of growth hormone secretion, but not in the morphine‐induced stimulation of prolactin secretion. In addition, there is a clear cross‐tolerance between dexmedetomidine and morphine in growth hormone secretion of the rat.
Inhibition of Low Density Lipoprotein Oxidation by Myrigalone B, a Naturally Occurring Flavonoid
Authors: Mathiesen Liv , Malterud Karl Egil , Nenseter Marit S. , Sund Reidar Bredo
Published: March 2009

Abstract: The influence of myrigalone B, a flavonoid from the fruit exudate of Myrica gale L. on Cu2+‐induced oxidation of low density lipoprotein from cholesterol fed rabbits was investigated. Myrigalone B was an effective antioxidant, as shown by its ability to dose‐dependently prolong the lag time for the formation of conjugated dienes. A 100% increase in lag time corresponds to a myrigalone B concentration of 1.4±1.1 μM. For α‐tocopherol, used as a reference, this effect corresponds to a concentration of 1.9± 1.2 μM. Myrigalone B also dose‐dependently reduced the maximum rate of formation of conjugated dienes, 1.4 μM causing a 15±5% reduction, but it had no influence on the maximal amount of conjugated dienes formed.
Interaction between Opioid and Muscarinic Receptors in the Guinea‐Pig Ileum Preparation: A Mathematical Model
Authors: Hustveit Olav
Published: March 2009

Abstract: Fentanyl and pethidine are opioid agonists and muscarinic antagonists in the guinea‐pig ileum preparation. In this preparation an opioid agonist reduces the release of acetylcholine. Therefore an opiate may influence the potency of an anticholinergic drug. A mathematical model was developed to characterize this putative interaction between opioid and muscarinic receptors. The model is based on the assumption that the drugs interact with the receptors in a competitive manner according to the law‐of‐mass action. Concentration‐response experiments were performed in the guinea‐pig ileum preparation to test the model. The mathematical model describes the concentration‐response curves very well and estimates the IC50 values for the two components with good precision. The study shows that an opioid agonist can potentiate the effect of an anticholinergic drug substantially. This is interesting with regard to the central anticholinergic syndrome. The conclusion is that the model describes the interaction adequately.
Milk Transfer and Neonatal Uptake of Coplanar Polychlorinated Biphenyl (PCB) Congeners in Mice
Authors: Sinjari Taha , Klasson‐Wehler Eva , Oskarsson Agneta , Darnerud Per Ola
Published: March 2009

Abstract:The selective accumulation of 3,3′,4,4′‐tetrachlorobiphenyl metabolites in late gestational foetal blood and soft tissues in mice as a result of administration of different coplanar polychlorinated biphenyl (PCB) congeners, is reported elsewhere. The situation in the nursing neonate after maternal exposure to the same congeners is now studied: The14C‐labelled congeners 3,V,4,4′‐telrachlorobiphenyl (IUPAC number CB‐77),3,3′,4,4′,5‐pentachlorobipheny] (IUPAC number CB‐126),3,3′,4,4′,5,5′‐hexachlorobiphenyl (IUPAC number CB‐169) (all threenon‐orthocongeners) and 2,3,3′,4,4′‐pentachlorobiphenyl (IUPAC number CB‐105) (mano‐orthocongener) were injected intravenously in lactating mice at day 11post partum. One day and four days later, milk and neonatal/maternal tissues and plasma radioactivity was monitored by liquid scintillation counting (dose: 2.0 μmol (20‐50 μCi)/kg body weight). In milk, CB‐126, ‐169 and ‐105 showed higher levels (1450‐2520 pmol/ml; one day after administration) than did CB‐77 (580 pmol/ml), and in neonates, the relative whole‐body levels of radioactivity (CB‐169 and ‐105 highest) were related to the levels seen in milk (probably the consequences of their metabolic persistence). The comparably high14C‐concentration found in neonatal liver (about 15,000 pmol/kg) after CB‐126 administration and in plasma (880 pmol/ml) after CB‐77 administration could be explained by binding to specific proteins. In general, neonatal mice had two to seven times higher plasma levels than those of their mothers. These results indicate that CB‐126, ‐169 and ‐105 are transferredviamilk to neonates in considerable quantity and are deposited mainly in neonatal liver, whereas CB‐77 is transferred in a comparably lower amount and accumulated in neonatal plasma. The lowerl4C‐levels in the NMRI mothers and offspring (about half of C57BL values in maternal and neonatal plasma), could possibly be explained by a differentiated metabolism of CB‐77 in these two strains.
Foetal Uptake of Coplanar Polychlorinated Biphenyl (PCB) Congeners in Mice
Authors: Darnerud Per Ola , Sinjari Taha , Jönsson Curt‐Johan
Published: March 2009

Abstract:Earlier studies (Darnerudet al. 1986) have shown that the Ah‐receptor binding polychlorinated biphenyl (PCB) congener 3,3′,4,4′‐tetrachlorobiphenyl (IUPAC number CB‐77) accumulated as hydroxy and methylsulphone metabolites in late gestational mice foetuses. In the present paper the foetal accumulation potential in mice of other dioxin‐like PCB congeners was studied: 3,3′,4,4′,5‐pentachlorobiphenyl, 3,3′,4,4′,5,5′‐hexachlorobiphenyl and 2,3,3′,4,4′‐pentachlorobiphenyl (IUPAC numbers CB‐126, CB‐169, CB‐105, to some extent dioxin‐like) were compared to results of CB‐77 (all congenersl4C‐labelled and in equimolar doses (2.0 umol/kg body wt.)). CB‐77 resulted in the comparatively strongest foetall4C‐accumulation, when measured in plasma or whole body homogenate four days after administration (day 17 of pregnancy); the plasma14C‐values (calculated as pmol/g wet wt.) were 760, 130, 60 and 40 for CB‐77, ‐126, 105 and ‐169, respectively, and the CB‐77 derived radioactivity in the foetal compartment was 3.6% of administered dose (i.e. a considerable portion of the remaining maternal body radioactivity). Thin‐layer chromatography (TLC) results, suggesting extensive CB‐77 metabolism and foetal metabolite uptake, support earlier findings. The effects of CB‐77 and CB‐169 on foetal 7‐ethoxyresorufin‐O‐deethylase (EROD) activities (day 17 of gestation; two days after 5 mg/kg body wt. dose (14.0‐17.0 Umol/kg body wt.)) was about 20 times lower than of CB‐126. In the dam, high radioactivity levels were observed in the liver and fat (highest concentrations found in CB‐126 and CB‐105, respectively). Strain comparison ‐ foetall4C‐uptake (four days after administration of CB‐77) in C57BL mice was almost five times higher than in NMRI ‐ may be correlated to earlier observed differences in EROD activities between these strains. The present results indicate that congener and strain differences exist regarding both foetal and maternal distribution patterns of coplanar PCB congeners and point out the difference in foetal disposition between CB‐77 and the other studied congeners.
Pharmacokinetics of Selective Serotonin Reuptake Inhibitors: Clinical Relevance
Authors: Catterson Mark L. , Preskorn Sheldon H.
Published: March 2009

Abstract:Selective serotonin reuptake inhibitors (SSRIs) are a safe and effective class of drugs for treatment of depressive and obsessive‐compulsive disorders. Among this class of drugs, pharmacodynamic actions, antidepressant efficacy and adverse effect profiles are remarkably similar. However, pharmacokinetic profiles of SSRIs are substantially different especially with respect to pharmacokinetically mediated drug‐drug interactions. For example, fluoxetine and paroxetine produce clinically significant inhibition of cytochrome P450 2D6 at their usually effective antidepressant dose, whereas citalopram, fluvoxamine or sertraline do not. There is also a substantial difference between SSRIs with respect to their capacity to inhibit other cytochrome P450 enzymes including 1A2, 2C19, 3A4 and possibly 2C9/10. The inhibition of these enzymes can reduce the clearance of concomitantly administered drugs which are dependent on oxidative metabolism mediated by these enzymes as a necessary prerequisite for their subsequent elimination. The accumulation of unusually high levels of such drugs can result in an increase in nuisance and/or more serious, even life‐threatening, adverse effects depending on the pharmacology of the co‐prescribed drug. Knowledge of these issues will enable clinicians to predict and make appropriate dose adjustments to avoid potential drug‐drug interactions that otherwise could result in toxicity.
Use of Rat and Human Liver Slices for the Detection of Steroid Hormone‐Induced DNA‐Adductsin vitroby Means of the32P‐Postlabeling Technique
Authors: Baumann Andreas , Kerdar Rasoul S. , Cramer Peter , Feser Werner , Blode Hartmut , Salomon Andreas , Kuhnz Wilhelm
Published: March 2009

Abstract:Precision cut liver slices from humans and rats were used to investigate the covalent binding of xenobiotics to the DNA by means of the32P‐postlabeling technique. Human liver slices were incubated with the structurally related steroid hormones chlormadinone acetate (5 μg/ml), cyproterone acetate (0.01‐5 μg/ml), megestrol acetate (5 μg/ml), and the positive control 2‐aminofluorene (0.01‐5 μg/ml), which is known for its marked ability to form DNA‐adductsin vivo. Rat liver slices were incubated with cyproterone acetate in concentrations of 0.1,1, and 5 μg/ml. The functional viability and metabolic activity of the slices were shown to be sufficiently maintained during the incubation time by measurement of the intracellular K+‐content and the metabolic turnover of the model substrate 7‐ethoxycoumarin, respectively. All three test substances and the control induced DNA‐adducts in human liver slices, however, with a different adduct pattern. While the total DNA‐adduct levels obtained with cyproterone acetate and megestrol acetate were in the same order of magnitude (on average 1000 DNA‐adducts/109nucleotides after incubation with 5 ug/ml), the relative adduct labeling calculated for chlormadinone acetate was about 400. Followingin vitroincubation of rat liver slices with cyproterone acetate, the relative adduct labeling values increased proportionally with increasing concentrations and added linearily toin vivogenerated DNA‐adducts. At the level of liver slices, different DNA‐adduct patterns were induced by cyproterone acetate in rat and man. In contrast to the finding of others, using rat hepatocytes, the relative adduct labeling values of cyproterone acetate and megestrol acetate were in the same order of magnitude after incubation with human liver slices. The present study indicates that liver slices are a useful tool to investigate thein vitroDNA‐adduct inducing potential of xenobiotics.
Primary Alcohols and Phosphatidylcholine Metabolism in Rat Brain Synaptosomal Membranes via Phospholipase D
Authors: Seidler Lothar , Kaszkin Marietta , Kinzel Volker
Published: March 2009

Abstract:Phospholipase D of rat brain synaptosomal membranes was tested with phosphatidylcholine as the substrate for its specificity in the use of primary alcohols as transphosphatidylation co‐substrates. The efficiency of the reaction was related to the hydrophobicity and the membrane penetrating capacity of the alcohol molecule. Phosphatidylalcohol formation could be detected up to 1‐octanol but not for alcohols with longer hydrocarbon chains (C9, C10). With increasing alcohol concentration the transphosphatidylation activity of the phospholipase D reached an optimum and then declined abruptly. Alcohol concentrations required for maximal transphosphatidylation reaction generally decreased with increasing hydrophobicities of the alcohols. Nevertheless 1‐butanol and 4‐chloro‐l‐butanol were the most efficient co‐substrates, sharing identical optimal conditions. Transphosphatidylation works at the cost of phosphatidic acid formation. Phosphatidic acid itself was transformed to diacylglycerol, probably by a contaminating phosphatidic acid phosphohydrolase.
Somatic Mutation Detection in Human Biomonitoring
Authors: Olsen Lone S. , Nielsen Lise Rud , Nexø Bjørn Andersen , Wassermann Karsten
Published: March 2009

Abstract: Somatic cell gene mutation arising in vivo may be considered to be a biomarker for genotoxicity. Assays detecting mutations of the haemoglobin and glycophorin A genes in red blood cells and of the hypoxanthine‐guanine phosphoribos‐yltransferase and human leucocyle antigenes in T‐lymphocytes are available in humans. This MiniReview describes these assays and their application to studies of individuals exposed to genotoxic agents. Moreover, with the implementation of techniques of molecular biology mutation spectra can now be defined in addition to the quantitation of in vivo mutant frequencies. We describe current screening methods for unknown mutations, including the denaturing gradient gel electrophoresis, single strand conformation polymorphism analysis, heteroduplex analysis, chemical modification techniques and enzymatic cleavage methods. The advantage of mutation detection as a biomarker is that it integrates exposure and sensitivity in one measurement. With the analysis of mutation spectra it may thus be possible to identify the causative genotoxic agent.
Characteristics of Behavioural Stimulant Effect of N‐Cyanomethylmethamphetamine, a Main Product of Smoking Methamphetamine Mixed with Tobacco: Evaluation by Ambulatory Activity in Mice
Authors: Kuribara Hisashi , Sekine Hitoshi , Nakahara Yuji
Published: March 2009

Abstract:N‐cyanomethylmethamphetamine is main product of smoking methamphetamine HCl (CAS code value: 537‐46‐2, molar mass: 185.70 g/mol) mixed with tobacco, and has a central stimulant action. The aims of this study were to assess in terms of ambulation in mice whether repeated administration of N‐cyanomethylmethamphetamine HC1 (molar mass: 211.70 g/mol) induced sensitization to its central stimulant effect, and whether there were cross‐sensitization from N‐cyanomethylmethamphetamine HC1 to methamphetamine HC1, and from methamphetamine HC1 to N‐cyanomethyl‐methamphetamine HCl. N‐cyanomethylmethamphetamine HCl 14.2 and 47.2 μmol/kg subcutaneously dose‐dependently accelerated ambulation of mice. Five administrations at 3 day intervals caused sensitization, the activity counts in the fifth administration being approximately 2.6 and 1.6 times, higher respectively, than those in the first administration. Furthermore, the mice repeatedly given 14.2 and 47.2 μmol/kg N‐cyanomethylmethamphetamine HC1 exhibited cross‐sensitization to methamphetamine HCl (10.8 μmol/kg subcutaneously). Whereas 1.4 and 4.7 μmol/kg N‐cyanomethylmethamphetamine HCl did not induce significant acceleration of the ambulation throughout the 5 repeated administrations, nor cross‐sensitization to methamphetamine HCl. On the other hand, the 5 repeated administrations of methamphetamine HCl (10.8 umol/kg) also caused sensitization to its ambulation‐increasing effect, and the activity count in the fifth administration attained approximately 2.0 times higher than that in the first administration. The mice given methamphetamine HCl demonstrated cross‐sensitization to 1.42‐14.2 umol/kg N‐cyanomethylmethamphetamine HC1. Haloperidol (CAS code value: 52‐86‐8, molar mass: 375.88 g/mol; 0.027‐0.80 umol/kg subcutaneously) dose‐dependently reduced the ambulation‐increasing effects of N‐cyanomethylmethamphetamine HCI and methamphetamine HC1 in the drug‐naive, and N‐cyanomethylmethamphetamine HCl‐ and methamphetamine HCl‐sensitized mice. These dose‐effect relationships were similar between groups. The present results suggest that N‐cyanomethylmethamphetamine HCl has a behavioural stimulant effect almost similar to that of methamphetamine HCl.
Pretreatment with Ischaemia Attenuates Acute Epirubicin‐Induced Cardiotoxicity in Isolated Rat Hearts
Authors: Schjøtt Jan , Olsen Hilde , Berg Kirsti , Jynge Per
Published: March 2009

Abstract: We investigated whether a brief ischaemic episode (ischaemic pretreatment) preconditioning might attenuate the acute cardiotoxicity of the anthracycline, epirubicin. Isolated rat hearts perfused at a constant flow rate of 10 ml/min. were preconditioned with 5 min. of global ischaemia and 10 min. of reperfusion (preconditoned hearts), or were perfused for 15 min. (control hearts). The hearts were then subjected to 20 min. of infusion with epirubicin (2 mg/ml) or vehicle by a side arm of the perfusion system at a rate of 0.1 ml/min. (0.2 mg epirubicin/min.). Attenuation of cardiotoxicity of a total dose of 4 mg of epirubicin was assessed by functional and metabolic parameters during infusion and during the following 30 min. recovery period. Cardiotoxic effects were reduced in preconditioned hearts compared to control hearts. Thus left ventricular developed pressure and heart rate product after 20 min. of epirubicin infusion was depressed to 27±7% (mean±S.D.) and 40±4% (mean±S.D.) of baseline values in the control group and the preconditioned group, respectively (P<0.05). Furthermore, we observed less contracture during epirubicin infusion and more effective reversal of contracture during the recovery period in the preconditioned hearts. Improvement in cardiac function was associated with a significantly lower (P<0.05) myocardial content of epirubicin in the preconditioned group at the end of the infusion period. We conclude that ischaemic preconditioning attenuates the acute cardiotoxicity of epirubicin, probably by reducing the myocardial accumulation of the anthracycline.
Nifedipine Reduces Thromboxane A2 Production by Platelets Without Changing Aggregation in Hypertensive Pregnancy
Authors: Manninen Auli
Published: March 2009

Abstract: Platelet aggregation and thromboxane A2 generation were studied in hypertensive pregnant women using normotensive non‐pregnant and pregnant controls. In hypertensive pregnancy, adrenaline‐ and adenosine diphosphate‐induced platelet aggregation was at the non‐pregnant level and lower than in normotensive pregnancy. Collagen‐induced aggregation was at a lower level in hypertensive pregnancy than in both control groups. Thromboxane generation during spontaneous clotting and in platelet‐rich plasma did not differ between the three groups. However, thromboxane generation was low during aggregation induced by small collagen concentrations in hypertensive pregnancy, but at higher collagen concentrations the difference between the groups disappeared. During nifedipine treatment (10 mg t.i.d.), aggregation and thromboxane production in platelet‐rich plasma induced by the three stimuli remained unaltered in hypertensive pregnancy, while thromboxane synthesis during spontaneous clotting was reduced. In nifedipine‐treated non‐pregnant controls, only EC80 for adrenaline‐induced aggregation decreased. In vitro, pharmacological concentrations of nifedipine inhibited platelet aggregation and thromboxane production. In conclusion, nifedipine reduces thromboxane generation in spontaneous clotting, without inhibiting platelet aggregation and thromboxane production in platelet‐rich plasma in hypertensive pregnancy. Reduced aggregability of platelet ex vivo may reflect their continuous activation and desensitiza‐tion in vivo in hypertensive pregnancy.
Minor Effect of Tolcapone, a Catechol‐ O‐Methyltransferase Inhibitor, on Extracellular Dopamine Levels Modified by Amphetamine or Pargyline: A Microdialysis Study in Anaesthetized Rats
Authors: Tuomainen Paivi , Törnwall Martti , Männistö Pekka T.
Published: March 2009

Abstract:In vivomicrodialysis was used to examine the effects of tolcapone (30 mg/kg) on dopamine metabolism in amphetamine (5 mg/kg) and pargyline (75 mg/kg) treated rats. Amphetamine‐ or pargyline‐induced decreases in the extracellular dihydroxyphenyl acetic acid (DOPAC) levels were counteracted by additional tolcapone. Tolcapone also decreased homovanillic acid effluxes below those caused by amphetamine or pargyline. However, dopamine effluxes were not further enhanced by additional tolcapone. These results show that central metabolism of dopamine can be modulated by catechol‐O‐methyltransferase (COMT) inhibition also without exogenous L‐DOPA. However, extracellular dopamine levels are not easily increased.
Cytotoxicity of Sanguinarine Chloride to Cultured Human Cells from Oral Tissue
Authors: Babich H. , Zuckerbraun H. L. , Barber I. B. , Babich S. B. , Borenfreund E.
Published: March 2009

Abstract: The in vitro cytotoxicity of sanguinarine chloride, a dental product used in the treatment of gingivitis and plaque, was compared using cell lines and primary cells from oral human tissues. For the established cell lines, sanguinarine chloride exhibited similar potencies to S‐G gingival epithelial cells and to KB carcinoma cells, whereas HGF‐1 gingival fibroblasts were more tolerant. However, a gingival primary cell culture was more sensitive to sanguinarine chloride than were the established cell lines. Detailed studies were performed with the S‐G cells. The 24‐hr midpoint (NR50) cytotoxicity value towards the S‐G cells was 7.6 uM, based on the neutral red cytotoxicity assay; vacuolization and multinucleation were noted. When exposed to sanguinarine chloride for 3 days, a lag in growth kinetics was first observed at 1.7 μM. Damage to the integrity of the plasma membrane was evident, as leakage of lactic acid dehydrogenase occurred during a 3 hr exposure to sanguinarine chloride at 0.1275 mM and greater. The cytotoxicity of sanguinarine chloride to the S‐G cells was lessened in the presence of an S9 hepatic microsomal fraction from Aroclor‐induced rats or by including fetal bovine serum (15%) in the exposure medium. Progressively increasing the pH from 6.0 to 7.8 enhanced the potency of sanguinarine chloride, presumably due to the enhanced uptake of the lipophilic alkanolamine form, as compared to that of the cationic iminium form.
The Effect of Ageing andin vitroExposure to Xylene and KC1 on [Ca2+]iin Synaptosomes from Rats Exposed Prenatally to Xylene
Authors: Edelfors S. , Hass U. , Ravn‐Jonsen A. , Lund S. P.
Published: March 2009

Abstract:Female rats (Mol: WIST) were exposed prenatally to 500 p.p.m. of technical xylene on days 7‐20. At the age of fourteen months the rats were sacrified and the synaptosomal fraction prepared forin vitrostudies. The cytosolic calcium concentration was measured using the FURA‐2 technique. The cytosolic calcium was increased in synaptosomes from old rats compared to those from rats at the age of three months, but no effect of prenatal exposure was seen. When synaptosomes were incubated with xylene, potassium or both, the cytosolic calcium concentration was changed identically in all groups of rats. When synaptosomes were incubated simultaneously to xylene and potassium a dramatical leakage of FURA‐2 was observed. The mechanisms behind the membrane leakage are discussed.
Effect of a Lignan‐Enriched Extract ofSchisandra Chinensison Aflatoxin B1 and Cadmium Chloride‐Induced Hepatotoxicity in Rats
Authors: Ip Sin Po , Mak Duncan H. F. , Li Pui Chun , Poon Michel K. T. , Ko Kam Ming
Published: March 2009

Abstract:Treatment of rats with a lignan‐enriched extract of the fruit ofSchisandra chinensiscould enhance hepatic antioxidant/detoxification system, as indicated by increases in hepatic reduced glutathione (GSH) level as well as hepatic glutathione reductase and glutathione S‐transferase activities. The hepatoprotective action was evident after aflatoxin β1or cadmium chloride (Cd) challenge.Schisandra chinensispretreatment protected against aflatoxin B1or Cd‐induced hepatocellular damage in rats. However, pretreating rats with α‐tocopherol acetate (vitamin E) did not protect against hepatic damage induced by both toxins. Results from the present as well as our previous studies demonstrate that the hepatoprotection afforded bySchisandra chiensispretreatment is not hepatotoxin specific.Schisandra chinensisseems to be more effective than vitamin E in protecting against aflatoxin B1and Cd toxicity. The mechanism of hepatoprotection afforded bySchisandra chinensispretreatment may involve facilitation of both antioxidant and detoxification processes in the liver.
Pharmacokinetics of Cefixime in Children with Urinary Tract Infections after a Single Oral Dose
Authors: Mamzoridi Katerina , Kasteridou Nicoletta , Peonides Alexander , Niopas Ioannis
Published: March 2009

Abstract: The pharmacokinetics of cefixime, a third‐generation broad‐spectrum cephalosporin, were determined following administration of a 8 mg/kg single oral dose of cefixime suspension to six children with urinary tract infections, ages from 6 to 13 years and weights from 17 to 60 kg. Blood samples for determination of plasma cefixime concentrations were obtained for up to 12 hr and complete urine collections were obtained for urinary excretion of unchanged parent drug for up to 24 hr after administration. Plasma and urine concentrations of cefixime were determined using a reversed phase HPLC assay and pertinent pharmacokinetic parameters were estimated by model‐independent standard methods. Mean peak plasma concentration was 4.04 ug/ml and was reached after 3.2 hr. The mean area under the plasma concentration‐time curve was 33.07 ug.hr/ml and the mean elimination half‐life was 3.91 hr. The mean apparent total clearance was 4.74 ml/min./kg and about 15% of the dose administered was recovered unchanged in urine. In conclusion, the estimated pharmacokinetic values of cefixime were comparable to those observed in healthy adult subjects based on equivalent mg/ kg doses. Plasma and urine concentrations of the drug were well above the reported minimal plasma and urinary concentrations for most common urinary tract pathogens for up to 12 and 24 hr after administration, respectively.
Neuronal Ion Channels as the Target Sites of Insecticides
Authors: Narahashi Toshio
Published: March 2009

Abstract:Certain types of neuronal ion channels have been demonstrated to be the major target sites of insecticides. The insecticide‐channel interactions that have been studied most extensively are pyrethroid actions on the voltage‐gated sodium channel and cyclodiene/lindane actions on the GABAAreceptor chloride channel complex. With the exception of organo‐phosphate and carbamate insecticides which inhibit acetylcholinesterases, most insecticides commercially developed act on the sodium channel and the GABA system. Pyrethroids slow the kinetics of both activation and inactivation gates of sodium channels resulting in prolonged openings of individual channels. This causes membrane depolarization, repetitive discharges and synaptic disturbances leading to hyperexcitatory symptoms of poisoning in animals. Only a very small fraction (~1%) of sodium channel population is required to be modified by pyrethroids to produce severe hyperexcitatory symptoms. This toxicity amplification theory applies to pharmacological and toxicological actions of other drugs that go through a threshold phenomenon. Selective toxicity of pyrethroids between invertebrates and mammals can be explained based largely on the responses of sodium channels and partly on metabolic degradation. The pyrethroid‐sodium channel interaction is also supported by Na+uptake and batrachotoxin binding experiments. Cyclodienes and lindane exert a dual action on the GABAAsystem, the initial transient stimulation being followed by a suppression. The stimulation requires the presence of the γ2 subunit. The suppression of the GABA system is also documented by CI‐flux and ligand binding experiments. It appears that the sodium channel and the GABA system merit continuing efforts for development of newer and better insecticides. Nitromethylene heterocycles including imidacloprid act on nicotinic acetylcholine receptors. Insect receptors are more sensitive to these compounds than mammalian receptors. Single‐channel analyses of the nicotinic acetylcholine receptor of PC12 cells have shown that imidacloprid increases the activity of subconductance state currents and decreases that of main conductance state currents. This may explain the imidacloprid suppression of acetylcholine responses.