bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of a Technical PCB Preparation and Fractions Thereof on Ethoxyresorufin O‐Deethylase Activity, Vitamin A Levels and Thymic Development in the Mink (Mustela vison)*
Authors: Brunström Björn , Håkanssorr Helen , Lundberg Katarina
Published: March 2009

Abstract:Clophen A50, a technical preparation of polychlorinated biphenyls (PCBs), was separated into four fractions; three containing chlorobiphenyls with 0, 1, or 2 to 4orthochlorines and one containing di‐ and tricyclic impurities such as naphthalenes and dibenzofurans. Clophen A50, the four fractions, and a synthetic mixture of the biologically most active non‐ortho‐chlorinated congeners (3,3′,4,4′‐tetra‐, 3,3′,4,4′,5‐penta‐, and 3,3′,4,4′,5,5′,‐hexachlorobiphenyl), were separately mixed in the feed and given to female mink during the reproductive season. The concentration of a given compound in the feed mixture was equivalent to its concentration in the feed mixed with Clophen A50. Hepatic 7‐ethoxyresorufinO‐deethylase (EROD) activity in adults was enhanced 2‐3 times by Clophen A50, the fractions containing non‐ or mono‐ortho‐chlorinated congeners, and the synthetic mixture. In neonatal kits delivered by females treated with non‐ or mono‐ortho‐chlorinated congeners, EROD was enhanced to about 30 times the control value. No live kits were delivered by the females treated with unfractionated Clophen A50. The fractions containing congeners with two to fourorthochlorines or di‐ and tricyclic compounds did not significantly induce EROD in either adults or kits. Clophen A50 reduced hepatic and pulmonary vitamin A contents in adult mink, while renal vitamin A was unaffected. Responses to the fractions containing the non‐ and mono‐ortho‐chlorinated congeners were similar to those obtained with Clophen A50. Their effects were, however, less pronounced, particularly with respect to the hepatic vitamin A reduction. The fractions containing congeners with two to fourorthochlorines and the di‐ and tricyclic compounds had no significant effects on tissue vitamin A contents. Thymocyte number was significantly reduced in kits exposed to the fractions containing non‐ or mono‐ortho‐chlorinated congeners. Thymocyte number was also lower in kits exposed to the synthetic mixture of non‐ortho‐chlorinated congeners than in control kits, but the difference was not statistically significant. To sum up, the non‐ and mono‐ortho‐chlorinated congeners in Clophen A50 enhanced EROD activities in adults and kits, reduced vitamin A concentrations in adults, and reduced thymocyte numbers in kits. Effects of the synthetic mixture of 3,3′,4,4′‐tetra‐, 3,3′,4,4′,5‐penta‐and 3,3′,4,4′,5,5′‐hexachlorobiphenyl were similar to those of the fraction from Clophen A50 containingnon‐ortho‐chlorinated congeners, and it is probable that the three coplanar congeners in the synthetic mixture, together with certain mono‐ortho‐chlorinated congeners, were largely responsible for the effects of Clophen A50 observed in this study.
In Vivo and in Vitro Toxicity of Fractionated Fish Lipids, with Particular Regard to their Content of Chlorinated Organic Compounds
Authors: Håkansson H. , Sundin P. , Andersson T. , Brunström B. , Dencker L. , Engwall M. , Ewald G. , Gilek M. , Holm G. , Honkasalo S. , Idestam‐Almquist J. , Jonsson P. , Kautsky N. , Lundberg G. , Lund‐Kvernheim A. , Martinsen K. , Norrgren L. , Personen M. , Rundgren M. , Stålberg M. , Tarkpea M. , Wesén C.
Published: March 2009

Abstract:Six different lipid matrices (the intact lipid (IL), four lipid fractions with different polarity, and the free fatty acids (FFAs) obtained by hydrolysis of the triacylglycerol (TAG) containing fraction) were obtained from salmon (Salmo salar) and eel (Anguilla anguilla), each collected at a contaminated and a comparatively uncontaminated catch site along the coast of Scandinavia. The lipid matrices were studied in toxicological test systems representing various biological functions of different organ systems from several species and trophic levels. The results were evaluated with particular respect to the concentrations of extractable organically bound chlorine (EOC1) in the matrices tested. In some test systems, the specimens with a higher EOC1 concentration appeared to be more toxic. For example, the TAG containing fraction (F2) from Idefjord eel, having a higher EOC1 content than F2 from Oslofjord eel, reduced the number and hatchability of eggs laid by zebrafish. Both IL and F2 of Idefjord eel increased mortality and reduced the oxygen/nitrogen‐ratio in blue mussels. Non‐polar compounds (F1) from Bothnian Sea salmon induced 7‐ethoxyresurofin O‐deethylase (EROD) activity in rainbow trout hepatocytes, whereas F1 from Senja salmon did not. F1 from Bothnian Sea salmon also reduced the number of T‐cells in foetal mouse thymus anlagenin vitrocompared with the cell number in anlagen exposed to F1 from Senja salmon. A positive correlation between EOC1 concentration and test response was found for EROD activity in rainbow trout hepatocytes and for ATP‐leakage in Erlich ascites tumour cells when testing the phospolipid containing fraction (F4). However, in most test systems the fish oils, irrespective of EOC1 content, were of low toxicity, and the observed effects need to be verified in future studies.
Effects of Calcium‐Channel Blockers on Cytosolic Free Calcium and Amylase Secretion in Rat Pancreatic Acini
Authors: Arita Yoshiyuki , Kimura Toshinari , Yazu Tsuyoshi , Ogami Yoshimitsu , Nawata Hajime
Published: March 2009

Abstract:We investigated the effects of verapamil and diltiazem on cytosolic free calcium and amylase secretion in rat pancreatic acini. Verapamil and diltiazem reduced a rise in cytosolic free calcium and amylase release stimulated by the maximal concentration (10‐5M) of carbachol in a dose‐dependent manner. High concentrations (500 μM) of verapamil and diltiazem inhibited both the initial and the sustained amylase secretion stimulated by 10‐5M carbachol. However, at low concentration (1 μM), they showed no effect on amylase secretion by 10‐5M carbachol. These calcium‐channel blockers did not affect calcium mobilization and amylase secretion stimulated by either caerulein or neuromedin C. Binding of3H‐N‐methylscopolamine to pancreatic acini was inhibited by verapamil and diltiazem in a dose‐dependent manner. These findings suggested that verapamil and dilitiazem reduced carbachol‐induced amylase secretion probably not due to their calcium‐channel blocking activities but due to their non‐competitive effects on the level of muscarinic receptors.
An Attempted Reversal of Cocaine‐Induced Analgesia by Dexamethasone
Authors: Pertovaara Antti , Kauppila Timo , Mecke Ernst
Published: March 2009

Abstract:Analgesia produced by systemic cocaine (20 mg/kg intraperitoneally) was not attenuated by dexamethasone (0.25–2.5 mg/kg) in the formalin or tail pinch test in rats. The result suggests that the activation of the corticotropin releasing factor‐adrenocorticotropin/β‐endorphin axis does not explain cocaine‐induced analgesia
Inhibition of Leukotriene Biosynthesis and Polymorphonuclear Leukocyte Functions by Orally Active Quinolylmethoxyphenylamines
Authors: Kirstein Dorte , Thomsen Mads Krogsgaard , Ahnfelt‐Renne Ian
Published: March 2009

Abstract: The N‐substituted quinolylmethoxyphenylamines, ETH603, ETH615 and ETH647, inhibited the formation of LTB4 in rat peritoneal leukocytes, human peripheral polymorphonuclear leukocytes and canine whole blood. In rat and human cells, the compounds also inhibited the formation of 5‐HETE and stimulated the synthesis of 15‐HETE. In rat leukocytes, the compounds were 15–30 times more potent inhibitors of LTB4 synthesis than nordihydroguaiaretic acid, but in canine whole blood they were significantly less potent, possibly due to protein binding. However, after oral administration of the compounds to dogs a long‐lasting inhibition of LTB4 production in peripheral blood was observed at serum concentrations much lower than those required in vitro. Furthermore, the compounds inhibited the LTB4‐directed chemotaxis and the phagocytosis of C. albicans blastospores by canine polymorphonuclear leukocytes both in vitro and following oral administration. The calcium ionophore A23187‐induced release of LTB4 in the peritoneal cavity of rats was also inhibited by systemic administration of the compounds. We therefore conclude that these novel quinolines are orally active 5‐lipoxygenase inhibitors which may accumulate in inflammatory cells in vivo, leading to potent inhibition of leukotriene biosynthesis and cell function.
Influence of Osmolality of Solutions Used for K+ Contraction on Relaxant Responses to Pinacidil, Verapamil, Theophylline and Terbutaline in Isolated Airway Smooth Muscle
Authors: Nielsen‐Kudsk Jens Erik , Nielsen Claus Brøckner , Mellemkjaer Søren
Published: March 2009

Abstract: Concentration‐relaxation profiles for pinacidil, verapamil, terbutaline and theophylline were studied in guinea‐pig trachealis contracted by two commonly applied techniques for K+ depolarization. All drugs were much less effective on contractions induced by hyperosmolar 124 mM K+ solution (added KCl) than on contractions elicited by an isoosmolar 124 mM K+ Krebs solution (substituted KCl). The maximal relaxant responses were (isoosmolar K+/hyperosmolar K+): pinacidil 100%/40%, verapamil 100%/60%, theophylline 100%/0%, terbutaline 50%/0%. Addition of mannitol to establish the same hyperosmolarity as with 124 mM KCl also produced contraction of guinea‐pig trachealis. Concentration‐relaxation curves for the drugs on mannitol‐induced contractions had close resemblance to those obtained in hyperosmolar 124 mM K+ solution. When contraction was elicited by 30 mM K+, pinacidil showed seven times higher relaxant potency in hyperosmolar compared to isoosmolar solution, whereas the relaxant responses to verapamil, theophylline and terbutaline were not influenced by osmolality. When K+ depolarization is used as a tool for evaluation of drug action in airway smooth muscle, the two different techniques produce dissimilar results. The influence of hyperosmolarity pec se appears to be an important and unwanted feature when K+ depolarization is produced by addition of KCl.
A Purified Recombinant Organophosphorus Acid Anhydrase Protects Mice Against Soman
Authors: Broomfield C. A.
Published: March 2009

Abstract: Since pharmacologic treatments of organophosphorus anticholinesterases (OPs) are nearing their practical limit other types of treatment are being sought. One approach is the prophylactic administration of scavengers that will detoxify OPs before they reach their critical target site. Using mice that were sensitized to OPs by depletion of their serum carboxylesterase with cresylbenzodioxaphosphorin oxide (CBDP), we have shown that animals pretreated intravenously with a purified organophosphorus acid anhydride hydrolase (parathionase) (0.10 mg per g body wt.) are not measureably affected by up to 34.4 ug soman per kg, a dose more than double that which is lethal to untreated animals. This result indicates that this approach is worthy of exploration and development for protecting military personnel and agricultural workers against OP intoxication.
Second Derivative of Developed Tension in Classifying Cardiotonics with Respect to Their Mechanisms of Action: Drugs Affecting cAMP Metabolism
Authors: Takalo Reijo , Malminiemi Kimmo , Wuorela Heikki , Vuorinen Pauli , Metsä‐Ketelä Timo
Published: March 2009

Abstract:The second derivative of developed tension (T”, d2T/dt2) has not come into common use in the analysis of cardiac contractility, although it has been shown to give additional information on the myocardial contraction‐relaxation cycle (CRC). In the present study a new way to use T”in the analysis of myocardial mechanics, including the time course of T”, is described. Profiles of the T”of the some drugs with established cardiotonic effects are presented. Experiments were carried out in spontaneously beating whole rat atria preparations. The effects of changing contraction frequency on the measured parameters were studied with electrically paced left atria. Qualitative inotropic effects of 1‐methyl‐3‐isobutylxanthine (MIX), theophylline, caffeine, milrinone, isoprenaline and forskolin were studied. Concentrations equief‐fective with respect to the force of contraction were tested. Inotropic profiles were evaluated at the time of maximal force of contraction. We found that methylxanthines have a mechanical behaviour quite distinct from other inotropic agents acting via cAMP. The effects of MIX were similar to those of theophylline in all respects. A tendency to increase the active relaxation phase of T”was a property common to methylxanthines. Caffeine also prolonged the phases of contraction, whereas MIX and theophylline have opposite effects. Milrinone in turn mimics the effects of isoprenaline and forskolin; abbreviation of the relaxation phase of T”was the feature most typical of them. Caffeine was the only agent which did not shorten the duration of CRC. The method proved valuable in basic research on drug effects on cardiac contractility.
Comparative Study of Cisplatin and Carboplatin on Pharmacokinetics, Nephrotoxicity and Effect on Renal Nuclear DNA Synthesis in Rats
Authors: Yasumasu Tetsuo , Ueda Toyofumi , Uozumi Jiro , Mihara Yukitaka , Kumazawa Joichi
Published: March 2009

Abstract: To clarify the difference in nephrotoxicity between cisplatin and carboplatin, the pharmacokinetics of platinum, renal function and nuclear DNA synthesis in renal cortical and outer medullary cells were studied in rats which had received cisplatin or carboplatin. Male Sprague‐Dawley rats were given either cisplatin or carboplatin intravenously at an equi‐toxic dose (LD10 or LD50) and were killed at various times within 7 days after the injection. Cisplatin bound to plasma proteins more avidly than carboplatin. Much more platinum was detectable in the renal nuclei after cisplatin injection than after carboplatin injection. BUN and serum creatinine levels in the rats treated with 8.5 mg/kg of cisplatin were significantly higher than in those treated with 100 mg/kg of carboplatin. Cisplatin markedly suppressed the renal nuclear DNA synthesis both in vivo and in vitro, when compared with carboplatin. It is concluded that the differences in nephrotoxicity between cisplatin and carboplatin are related to their different inhibitory effects on nuclear DNA synthesis in the renal cells.
Slow Kinetic Property of Mexiletine in Guinea Pig Atrium
Authors: Shirayama Takeshi , Inoue Daisuke , Inoue Miho , Miyazaki Hiroshi , Tatsumi Tetsuya , Asayama Jun , Katsume Hiroshi , Nakagawa Masao
Published: March 2009

Abstract:We studied the onset and offset of use‐dependent block (UDB) of maximum rate of rise of action potential (V̇max) with 3 × 10–5M mexilietine in guinea pig left atrium. A large decrease of V̇max was observed between the first and the second excitation when the preparations were stimulated at 4Hz after two minutes of rest period. UDB after the second excitation developed slowly to reach steady state within 30 sec. These two onset rates were 1.016 ± 0.055 and 0.070 ± 0.009/action potential. Recovery process was also fitted with two exponential equations. The time constant of the fast recovery was 528 ± 23 msec, and the slow one was 3099 ± 435 msec. The relative contribution of the slow component was 38.3 ± 2.6% in the onset and 29.7 ± 3.1% in the recovery. In spite of elevated maximum diastolic potential at 4 Hz stimulation, the relationship between resting membrane potential and V̇max disclosed voltage‐dependent block of V̇max was no more than 5%. It is concluded that mexiletine has a slow kinetic component as well as a fast one. When atrial muscle is depolarized, V̇max decreases further. Therefore, mexiletine may be more effective against the atrial arrhythmias than predicted previously.
Alteration of Pancreatic B‐Cells in Wistar Rats Treated with Non‐Diabetogenic Doses of Cyclosporin A
Authors: Hahn H. J. , Laube R. , Lucke S. , Besch W.
Published: March 2009

Abstract: We have investigated the effect of non‐immunosuppressive cyclosporin A (CS‐A) doses on glucose tolerance, pancreatic insulin content, insulin content of isolated islets and insulin secretion in vitro in response to glucose. Within 12 weeks animals treated permanently with a dose of 2.5 mg CS‐A/kg b.wt. developed glucose intolerance (but not hyperglycaemia) accompanied by a decrease of pancreatic insulin content due to a decrease of islet insulin content, whereas the relative B‐cell volume density was.not changed. Isolated islets obtained from rats treated for 4 weeks had a diminished sensitivity for glucose, whereas islets obtained from animals treated for > 4 weeks showed a diminished half‐maximum and maximum secretion rate. Rats treated for 12 weeks with 1.25 mg CS‐A/kg b.wt. developed an impaired glucose tolerance after 8 weeks accompanied by a diminished pancreatic insulin content. Despite continued treatment the pancreatic insulin content was able to increase and the glucose tolerance to normalize, indicating an adaptation of pancreatic B‐cells to CS‐A. The results support the theory that a potential toxic effect of cyclosporin A can be diagnosed by functional tests (e.g. insulin secretion in response to a stepwise increase of glucose) before the irreversible (e.g. morphological) alterations occur.
Evidence that Drug Binding to Non‐Adrenergic [3H]‐Idazoxan Binding Sites (I‐Receptors) Occurs to Interacting or Interconvertible Affinity Forms of the Receptor
Authors: VVikberg Jarl E. S. , Uhlén Staffan , Chhajlani Vijay
Published: March 2009

Abstract:Characterization of [3H]idazoxan binding to guinea pig kidney membranes showed that ~ 90% bound to non‐adrenergic I‐receptors and ~ 10% to α‐adrenoceptors. I‐Receptors could be studied separately by including 3μM rauwolscine to the assay. During these conditions 22 different compounds out of 29 (including imidazoline and guanidinium compounds) generated biphasic or shallow competion curves (Hill coefficients down to 0.57), for which computer modelling suggested that drugs bound to two sites with different affinities. However, the proportion of sites varied considerably depending on which drug was used as competitor; the variation being from ~ 50/50% to ~ 8/92% and analysis of variance clearly indicated that the variation of proportions of sites could be attributed to an effect induced by the drugs which indicated that the sites were dynamically formed or modulated by the presence of the drug. A few drugs (guanabenz, (–)‐medetomidine, phentolamine, clemastin, prazosin and idazoxan itself) yielded steep uniphasic curves (Hill coefficients near unity) which were resolved only into one site fits. One drug (detomidine) yielded supersteep competition curves (Hill coefficient 1.29), the data being reminiscent of positive cooperativity. In another set of experiments attempts were made to block one of the affinity forms of the I‐receptor with histamine, a compound which had grossly different affinities for the two I‐receptor sites, and competition curves were then obtained using other drugs which also seemed to distinguish between the two sites. Computer analysis of experimentally obtained as well as simulated, computer generated, competition curves clearly showed that the kidney I‐receptors did not exist in two independent non‐interacting forms. Instead the data suggested that the I‐receptor was composed of interacting or interconverting receptor entities with different affinities for drugs. Monovalent cations such as Cs+or NH4+were found to be powerful inhibitors of [3H]idazoxan binding to the kidney I‐receptors, the ions decreasing both the apparent Bmaxand affinity of the ligand for the receptor. The cations also decreased the affinities of UK‐14,304 for both the high and low affinity forms of the I‐receptor, but the apparent proportions of sites were not at all affected by the ions. Moreover, ligand binding to kidney I‐receptor were not at all affected by non‐hydrolyzable guanine nucleotides. It is suggested that the binding data reflects functional properties of the I‐receptor protein.
Covalent Binding of Food Carcinogens MeIQx, MeIQ and IQ to DNA and Protein in Microsomal Incubations and Isolated Rat Hepatocytes
Authors: Wallin Hakan , Holme Jam A. , Alexander Jan
Published: March 2009

Abstract: The metabolic activation of 14C‐labelled food carcinogens 2‐amino‐3, 8‐dimethylimidazo[4,5‐f]quinoxaline (MeIQx), 2‐amino‐3,4‐dimethylimidazo[4, 5‐f]quinoline (MeIQ) and 2‐amino‐3‐methylimidazo[4, 5‐f]quinoline (IQ) to macromolecular bound species was studied in microsomal and hepatocellular incubations. Several data indicated that the covalent binding was dependent on P450 enzymes: It was dependent on NADPH, it was induced many times by the P450 IA1 and IA2 upregulators β‐naphthoflavone and polychlorinated biphenyls, and was inhibited by the P450 IA1 and IA2 inhibitor α‐naphthofiavone. In both hepatocellular and microsomal incubations the three compounds bound with similar efficiency, with IQ being somewhat more potent compared to MeIQx and MeIQ. The binding appeared to follow saturation kinetics with Km values less than 20 μM. In incubations with hepatocytes the compounds bound to both cellular DNA and to bovine serum albumin in the medium. The fact that 13–26% of total adducts were formed with bovine serum albumin, indicates that reactive metabolites of the compounds may be transported and react at distant sites from their formation without any further activation.
Caffeine Moderately Antagonizes the Effects of Triazolam and Zopiclone on the Psychomotor Performance of Healthy Subjectsf
Authors: Mattila M. E. , Mattila M. J. , Nuotto E.
Published: March 2009

Abstract:To determine whether caffeine antagonizes the decremental effects of triazolam and zopiclone on human performance, oral single doses of 0.250 mg triazolam, 7.5 mg zopiclone, or respective placebos, with and without 300 mg caffeine, were given to parallel groups of student volunteers in two double‐blind studies. Objective tests and subjective visual analogue ratings were done at baseline and 30 min. and 90 min. after the intake. In Study I, triazolam produced drowsiness at 30 min. but did not differ from the placebo in other tests. Caffeine induced alerting effects in various tests and differed from triazolam in some (digit substitution, drowsiness, calmness, mental slowness) but not all variables measured. Caffeine and triazolam were interpreted as being antagonists. In Study II, zopiclone impaired digit substitution and flicker fusion, produced exophoria and lowered systolic blood pressure. Caffeine differed from zopiclone in several test functions, but it also differed from caffeine + zopiclone whereas zopiclone differed from caffeine + zopiclone only in two tests (Maddox wing, systolic blood pressure). Thus, zopiclone counteracted the effects of caffeine more easily than caffeine counteracted the decremental effects of zopiclone. We conclude that triazolam may not differ importantly from diazepam as regards their antagonism towards caffeine, whereas further research on the antagonism between zopiclone and caffeine needs to be done.
Inhibitory Effect of Dicumarol on the Excitability of the Sarcolemma of Skeletal Muscle
Authors: Røed Asbjørn
Published: March 2009

Abstract: Dicumarol (7.5 × 10–6 M – 7.5 × 10–5 M) inhibited the twitches and the simultaneously recorded electromyogram of the indirectly stimulated rat diaphragm preparation. The directly stimulated curarized preparation was inhibited in a similar way. Accordingly, the excitability of the sarcolemma was inhibited by dicumarol. The inhibitory effect was irreversible upon washing. Intracellular microelectrode recordings disclosed that the inhibitory effect was accompanied by a depolarization, and the inhibition was potentiated in high K+ (9.5 mM) solution. In addition, the ability of the preparations to produce a depolarization contracture with KCl (100 mM) was inhibited by dicumarol. Therefore, a part of the inhibitory effect might be caused by the depolarization. On the other hand, subthreshold direct stimulation disclosed that the inhibitory effect might be due to an increase of the threshold. However, a lack of synergistic interaction with lidocaine (0.2 mM) showed that this effect of dicumarol was probably not a membrane stabilizing or local anaesthetic effect.
Studies on the Mechanism of Acetonitrile Toxicity I: Whole Body Autoradiographic Distribution and Macromolecular Interaction of 2–14C‐Acetonitrile in Mice*
Authors: Ahmed Ahmed E. , Loh Jiann‐Ping , Ghanayem Burhan , Hussein Gamal I.
Published: March 2009

Abstract: Acetonitrile, a commonly used solvent is known to cause central nervous system dysfunctions. In order to gain an insight onto the mechanism of acetonitrile toxicity, we studied the kinetics of acetonitrile distribution in mice. Male ICR mice were given a tracer dose of 2–14C‐acetonitrile intravenously (60 μ mol/kg or 684 μCi/kg, spec. act. 11.4 mCi/ mmol). At various time intervals (5 min., 0.5, 1, 4, 8, 24 and 48 hr) after treatment, mice were anaesthetized and frozen by immersion in a dry ice/hexane mixture, or they were dissected for collection of organs and tissues. Frozen mice were processed for whole body autoradiography, which allows the detection of non‐volatile metabolites of acetonitrile at their sites of accumulation. Covalent binding of acetonitrile metabolites in tissues was determined using trichloroacetic acid followed by ethanol/ether extraction techniques. Whole body autoradiography revealed heavy localization of acetonitrile metabolites in the gastrointestinal tissues and bile. At 5 min., the highest levels of radioactivity occurred in the liver and kidney; levels declined over time. At 24 and 48 hr, acetonitrile derived radioactivity were detected in the gastrointestine, thymus, liver and male reproductive organs. Covalent binding studies at 24 and 48 hr after treatment indicated that 40–50% of the total radioactivity present in the liver was bound to the macromolecular fractions of the tissues. The radioactivity contents of other organs were, in large part (40–50% of total), present in the lipid fraction of the tissue. Our studies suggest that the irreversible association with tissues of radioactivity derived from 2–14C‐acetonitrile is due to the metabolic activation of acetonitrile and the covalent interaction of reactive metabolite(s) with lipid and macromolecular fractions of the cell.
Effects of Dietary Fat Composition on Activities of the Microsomal Ethanol Oxidizing System and Ethanol‐Inducible Cytochrome P450 (CYP2E1) in the Liver of Rats Chronically Fed Ethanol
Authors: Takahashi Hisao , Johansson Inger , French Samuel W. , Ingelman‐Sundberg Magnus
Published: March 2009

Abstract:We studied the effects of dietary fat composition on the activities of the microsomal ethanol oxidizing system (MEOS), paranitrophenol hydroxylase (PH) activity and ethanol‐inducible cytochrome P450 isozymes (CYP2E1 and CYP2B1) in the liver of rats to determine the role of this ethanol metabolizing pathway in the pathogenesis of alcoholic liver disease (ALD). Wistar male rats were pair‐fed a liquid diet, containing either tallow (TF) or corn oil (CF) as the fat component, and ethanol or an isocaloric amount of dextrose, through an implanted intragastric cannula. Liver pathology of rats fed ethanol (CF‐ALC) and CF diet showed severe fatty change whereas the rats fed TF‐alcohol and the TF and CF controls did not. MEOS activity of the CF‐ALC group was 8 times of that in the CF‐CTL group (P < 0.01). In TF‐ALC rats, MEOS activity was increased to 2.6 times compared to that of TF‐CTL (P< 0.01). ApoCYP2E1 in CF‐ALC and TF‐ALC were 818 ± 63 and 433 ± 17 pmol/mg protein, respectively, and these values were significantly higher when compared with those of the pair‐fed controls (P< 0.005). In contrast, apoCYP2B1 was increased to an equal degree in both CF‐ALC and TF‐ALC. When PH‐activity was measured, the level of activity on TF‐ALC rats did not differ from that of CF‐ALC rats. Thus, ethanol‐induction of apoCYP2Bl (2 x) and PH (6–8 x) were the same for CF and TF (2 x); but not for apoCYP2E1 (21 and 8 x, respectively) and MEOS activity (8 and 2.6 x, respectively). These results indicate that the dietary effect on the expression of CYP2E1 correlates with the induction of centrilobular liver damage seen in the corn oil fed rats. The centrilobular distribution of this isozyme also correlates with the site of liver cell injury further suggesting a pathogenic link to alcohol‐induced cell injury.
Studies of Embryotoxicity and the Incidence of External Malformations after Continuous Intravenous Infusion of α‐Chaconine in Pregnant Rats
Authors: Hellenäs Karl‐Erik , Cekan Eva , Slanina Premysl , Bergman Kerstin
Published: March 2009

Abstract: Embryotoxicity and effects on the incidence of external malformations of the major potato glycoalkaloid α‐chaconine (α‐cha) were studied in rats. Pregnant Sprague‐Dawley rats (n = 17) were given a continuous intravenous infusion of α‐cha via implanted osmotic minipumps (1.7 mg/kg/day), to maintain a stable blood concentration on days 6–13 of gestation. Control animals recevied physiological saline solution or were left untreated, respectively. Blood serum levels of α‐cha were monitored at selected time intervals during the treatment using a specific HPLC method. The foetal body weights and the number of resorbed or dead foetuses per litter in the α‐cha treated group were not significantly different from the control groups. No case of malformation was detected among 143 foetuses inspected in the treated group. The average maternal blood serum concentration of α‐cha measured during the experiment was 340 ng/ml. This is more than 20 times the average peak serum level previously reported for human volunteers after intake of potatoes with a total glycoalkaloid content at the upper safe limit for acute adverse effects. The results support the view that potato glycoalkaloids, at levels normally found in potatoes, do not present a risk for teratogenicity in humans.
Gentamicin Nephrotoxicity in Rat: Some Biochemical Correlates
Authors: Ali B. H. , Gayoum A. A. Abdel , Bashir A. A.
Published: March 2009

Abstract:The present work examines the effect of treatment of rats with graded doses of the aminoglycoside antibiotic gentamicin on the concentration of reduced glutathione (GSH) and diamine oxidase (DAO) activity in the kidney, and DAO activity, creatinine and magnesium (Mg) in the plasma. The animals were given the antibiotic intramuscularly in doses of 20, 40, and 80 mg/kg/day for 6 days, and were killed 24 hr after the last injection. In another experiment rats were injected intramuscularly with gentamicin at a dose of 80 mg/kg/day for 6 days and were killed 1, 7 or 14 days after the last injection, and the above parameters were measured. Gentamicin reduced the body weights of rats in a dose‐dependent manner. The weight reductions were most marked on days 4, 5 and 6 of the treatment. The body weights gradually recovered on withdrawing of the drug, and by day 14, they were not significantly different from those of the controls. Gentamicin produced significant and dose‐dependent decreases in the renal concentration of GSH. Seven and 14 days after withdrawing the drug, the GSH concentrations were still significantly below that of the controls. Plasma Mg concentrations were significantly decreased, and plasma creatinine concentrations significantly increased by gentamicin. These effects persisted 7 and 14 days after cessation of treatment. Plasma DAO activity was not detectable in the control or gentamicin‐treated rats. In the renal cortex, the activity of the enzyme, measured 1, 7 and 14 days after the treatment, was not significantly different from that of the control. Histopathologically, the drug produced dose‐dependent proximal renal tubular necrosis. Seven days after withdrawal of gentamicin, the degree of necrosis was less marked, and 14 days after drug withdrawal, renal histology was apparently normal.
Supersensitivity to the Antinociceptive Effect of a 5‐HT1Receptor Agonist after Lesion of Raphe‐Spinal Serotonergic Neurones
Authors: Eide Per Kristian , Hole Kjell , Broch Ole Jacob
Published: March 2009

Abstract:The actions of the 5‐hydroxytryptamine type‐1B (5‐HT1) receptor agonist 1(m‐chlorophenyl)piperazine (mCPP) on response latencies in the tail‐flick test and tail skin temperature were examined in mice after pretreatment with the 5‐HT neurotoxin, 5,6‐dihydroxytryptamine (5,6‐DHT). All the compounds were given intrathecally. The level of 5‐HT in spinal cord was reduced by 79% 4 days after intrathecal injection of 5,6‐DHT (10 μg). There was a significant relationship between the tail‐flick latency and tail skin temperature, and the reduced baseline tail‐flick latencies induced by 5,6‐DHT were non‐significant after the change in skin temperature was taken into account. Intrathecal mCPP (5 μg) significantly increased the tail‐flick latency and significantly reduced the tail skin temperature in 5,6‐DHT pretreated animals when compared to control animals. These differences in tail‐flick latencies could not be explained by alterations in skin temperature. The results provide evidence that neurotoxic lesion of descending 5‐HT pathways induces supersensitivity to the antinociceptive effect of 5‐HT1receptor stimulation.
Amiloride Derivatives as Blockers of Na+/Ca2+Exchange: Effects on Mechanical and Electrical Function of Guinea‐Pig Myocardium
Authors: Wettwer Erich , Himmel Herbert , Ravens Ursula
Published: March 2009

Abstract:The amiloride derivatives, 2′,3′‐benzobenzamil (BB), 3′,4′‐dichlorobenzamil (DCB), and 5‐(N‐4‐chlorobenzyl)‐2′,4′‐dimethylbenzamil (CBDB) are known as inhibitors of the Na+/Ca2+exchange. This kind of drug action was recently suggested to be a new inotropic mechanism. In guinea‐pig myocardium, we have studied the inotropic and the accompanying electrophysiological effects of the three compounds in order to assess their selectivity of action. In left atria and in papillary muscle, force of contraction increased with DCB and CBDB (atria only) at a high concentration (5 × 10‐5− 10‐4mol/l) and after long exposure time, whereas BB produced a negative inotropic effect. In the isolated perfused Langendorff heart, the amiloride derivatives tested decreased spontaneous heart rate and force of contraction and prolonged the duration of contraction. In isolated cardiac myocytes, sodium current, calcium current and the delayed rectifier were reduced by concentrations of BB, DCB and CBDB similar to the IC50values reported for the inhibition of the Na+/Ca2+exchange. Our results demonstrate that the amiloride derivatives have multiple sites of action. It is concluded that more specific modulators of the Na+/Ca2+exchange are required in order to define their contribution to the regulation of contractile activation of the heart.
GEA 857 Blocks Potassium Channels in the Membrane and, Thereby, Prolongs Muscarinic Cholinergic Responses in N1E‐115 Neuroblastoma Cells
Authors: Hedlund Britta , Ögren Sven Ove
Published: March 2009

Abstract: GEA 857 [2‐(4‐chlorophenyl)‐1,1‐dimethylethyl 2‐amino‐3‐methylbutanoate], a structural analogue of the serotonin (5‐HT) uptake inhibitor alaproclate but without effects on the 5‐HT uptake, was shown to potentiate muscarinic cholinergic responses in N1E‐115 neuroblastoma cells. In intracellular recording experiments, GEA 857 (1 μM) increased the cell input resistance and prolonged the action potential. It also prolonged the cellular response to carbachol acting on muscarinic receptors in a manner mimicked by potassium channel blockers such as 4‐aminopyridine and TEA. GEA 857 did not affect the carbachol stimulated uptake of 45Ca, but depressed the carbachol activated outflow of 86Rb from neuroblastoma cells. The conclusion drawn from these results is that GEA 857 reduces potassium conductances in the membrane in N1E‐115 neuroblastoma cells and, thereby, prolongs muscarinic agonist‐induced responses.
Obidoxime Augments the Positive Inotropic Effect of Phosphamidon on the Isolated Working Rat Heart
Authors: Ben‐Haim Shlomo A. , Ben‐Ami Haim , Hayam Gal , Taitelman Uri , Edoute Yeouda
Published: March 2009

Abstract: The present study was designed to determine modulation of the direct inotropic effect of an anticholinesterase organophosphorus compound, phosphamidon, by the reactivator obidoxime. We investigated the effects of phosphamidon (n = 9), obidoxime (n = 5), and their combination (n = 5) on the mechanical and energetic indices of left ventricular function, in the isolated working rat heart model. Phosphamidon at a concentration range of 10‐6‐10‐3 M had a positive inotropic effect. Obidoxime at a concentration range of 10‐6‐10‐3 M had no significant effect on heart rate, but did have a statistically significant positive inotropic effect on end‐systolic pressure, cardiac output, mean left ventricular pressure, and maximal time derivative of left ventricular pressure (dP/dtmax) (P<0.01). Perfusion with 10‐3 M obidoxime caused a 19% increase in left ventricular stroke work and a 31% increase in total pressure‐volume area. Perfusion with phosphamidon and obidoxime at concentrations ranging from 10‐6 to 10‐3 M resulted in a more intense inotropic response than the separate drug effects. At the highest combined concentrations tested, cardiac output increased by 60%, left ventricular stroke work increased by 100%, and left ventricular total pressure volume area increased by 111% of their control values (P<0.001). We conclude that obidoxime augments the positive inotropic effect of phosphamidon on the isolated working rat heart.
The Involvement of Sigma and Phencyclidine Receptors in the Action of Antipsychotic Drugs
Authors: Lang Aavo , Vasar Eero , Soosaar Andres , Harro Jaanus
Published: March 2009

Abstract:An atypical antipsychotic drug clozapine and a selective sigma antagonist BMY 14802 were significantly less effective in the behavioural experiments (against apomorphine, d‐amphetamine and MK‐801), as well in the radioligand binding studies against3H‐spiperone (dopamine2‐receptors) and3H‐haloperidol (sigma receptors) in the rat brain, as compared to a typical antipsychotic compound haloperidol. Contrary to haloperidol and BMY 14802, clozapine was a relatively selective antagonist of MK‐801‐induced motor excitation in the mouse. A nearly 3‐fold lower dose of clozapine was needed to block the effect of MK‐801 (6.4 μmol/kg) as compared to the action of amphetamine (17 μmol/kg). Haloperidol and clozapine, but not BMY 14802, antagonized apomorphine‐induced aggressiveness in the rat. After long‐term treatment (for 15 days) with BMY 14802 (10 mg/kg daily), haloperidol (0.5 mg/kg daily) and clozapine (10 mg/kg daily) the motor depressant effect of apomorphine (0.15 mg/kg) was reversed. Chronic haloperidol treatment, but not administration of BMY 14802 and clozapine, increased the number of dopamine2‐receptors in the rat brain. BMY 14802 caused upregulation of sigma receptors in frontal cortex, whereas haloperidol induced the opposite change in cerebellum. Repeated treatment with clozapine significantly augmented the motor stimulating effect of MK‐801 in rats. Simultaneously with a behavioural change the density of3H‐TCP binding sites in the rat forebrain was elevated after long‐term treatment with clozapine, probably indicating the involvement of PCP binding sites at NMDA channel in the action of clozapine.
Tri‐n‐butyltin Increases Intracellular Ca2+ in Mouse Thymocytes: A Flow‐Cytometric Study Using Fluorescent Dyes for Membrane Potential and Intracellular Ca2+
Authors: Chikahisa Lumi , Oyama Yasuo
Published: March 2009

Abstract: Effects of tri‐n‐butyltin (TBT) on mouse thymocytes were examined using a flow‐cytometer and fluorescent dyes for membrane potential and intracellular Ca2+ ([Ca2+]i). TBT at concentrations from 1 × 10‐7 M to 3 × 10‐7 M caused hyperpolarization in thymocytes during 30 min. after drug application in a time‐ and dose‐dependent manner. Further increase in TBT concentration (to 1 × 10‐6 M) made hyperpolarization of thymocytes more profound within 5 min. after application, thereafter gradually depolarized them during the next 25 min. TBT at 3 × 10‐8 M or more (up to 1 × 10‐6 M) increased the [Ca2+]i of thymocytes. After reaching maximum [Ca2+]i at the various TBT concentrations used within 5 min. after drug application, the [Ca2+]i slightly decreased in a time‐dependent manner. Effects of TBT on membrane potential and the [Ca2+]i were greatly reduced under nominal external Ca2+ ‐free condition. Results suggest that TBT can promote Ca2+ ‐influx to thymocytes, resulting in hyperpolarization by activation of Ca2+ ‐dependent K+ current. The increase in [Ca2+]i by TBT may be related to its cytotoxic action on thymocytes.
The Effect of Chloral Hydrate and its Metabolites, Trichloroethanol and Trichloroacetic Acid, on Bilirubin‐Albumin Binding
Authors: Onks David L. , Robertson Alex F. , Brodersen Rolf
Published: March 2009

Abstract: Chloral hydrate is used as a sedative in infants requiring ventilatory support. The metabolites, trichloroethanol and trichloroacetic acid, accumulate in the serum and are protein bound. The possibility that these chemicals might compete with bilirubin for albumin binding was tested using the peroxidase method and a dialysis rate method. Chloral hydrate and trichloroethanol had no effect on bilirubin‐albumin binding. Trichloroacetic acid affects bilirubin‐albumin binding but to a degree that would be dangerous only in infants with an unusual accumulation of this metabolite.
Characterisation of Dopamine and Serotonin Uptake Inhibitory Effects of Tetrahydroaminoacridine in Rat Brain
Authors: Jossan Sukhwinder Singh , Adem Abdu , Winblad Bengt , Oreland Lars
Published: March 2009

Abstract:The effects of 1,2,3,4‐tetrahydro‐9‐aminoacridine (THA) on uptake rates of radioactive 5‐hydroxytryptamine (5‐HT) and dopamine were investigated in rat diencephalon and striatal homogenates, respectively. Six and eight μM of THA were needed to inhibit 50% of dopamine and 5‐HT uptake rates. Kinetic parameters, Kmand Vmax, using six different concentrations of dopamine and 5‐HT were estimated in the presence or absence of THA. A significant decrease in Vmaxwithout any change in Kmvalues was observed for both dopamine and 5‐HT in the presence of THA. The results show that THA is a non‐competitive uptake inhibitor of dopamine and 5‐HT in the nerve terminals. The re‐uptake blocking effect of THA on dopaminergic and serotonergic neurones, following THA treatment, might lead to increased levels of these monoamines in brains of Alzheimer patients and contribute in the therapeutic effects of the drug.
Dose Dependent Induction of the Microsomal Monooxygenase Aryl Hydrocarbon Hydroxylase in Isolated Peripheral Blood Monocytes: The Influence of Age
Authors: George Graeme , Woodhouse Ken
Published: March 2009

Abstract: The induction of the microsomal monooxygenase benzo(α)pyrene hydroxylase was investigated in isolated peripheral blood monocytes from young and old donors, after exposure to different concentrations of benzanthracene as an inducing agent. The sensitivity of the cells to the inducing stimulus was not dependent on the age of the donor. The mechanisms underlying impaired monooxygenase induction in the elderly remain to be clarified.
Mechanical Effects of Some Prostanoids on Isolated Human Oesophageal Submucosal Veins
Authors: Madsen G. , Tattrup A. , Andersson K.‐E. , Forman A.
Published: March 2009

Abstract: The effects of prostaglandins E1, E2, F2α, prostacyclin, and the thromboxane A2‐mimic U46619 were investigated on isolated human oesophageal submucosal veins from the oesophageal body and the oesophagogastric junction. U46619 most potently, but also PGF2α produced venocontraction without differences between preparations from the oesophageal body and the oesophagogastric junction. PGE1 and prostacyclin caused relaxation of vessels precontracted with U46619 (10‐9 M). PGE2 induced either contraction or relaxation, but biphasic effects in the same vessel segment were not seen. Indomethacin 10‐6 M inhibited the contractile responses to both noradrenaline and K+ (124 mM), suggesting that the agonists induced synthesis or release of vasoconstrictor prostanoids. Prostanoids exert potent mechanical effects in submucosal oesophageal veins and may be of physiological importance.
Interaction between Ciprofloxacin and Thiopental in the Central Nervous System of the Male Rat
Authors: Schliamser Silvia E. , Broholm Karl‐Axel , Wahlstrom Goran
Published: March 2009

Abstract: The effect of intravenous ciprofloxacin (CPX) pretreatment on the kinetics and brain sensitivity for thiopental was studied in male rats using a previously developed electroencephalographic (EEG) threshold method. Thiopental was administered intravenously with constant infusion rate. Immediately after the appearance of the first burst suppression of 1 sec. or more (the “silent‐second”) in the EEG the infusion was stopped and the rats were killed by decapitation. The dose of thiopental needed to reach the criterion of silent‐second was slightly reduced in ciprofloxacin pretreated rats when compared with saline pretreated controls. One rat that developed seizures after CPX pretreatment needed a considerably reduced dose of thiopental to induce the silent‐second. The serum concentrations of thiopental were markedly reduced in the experimental group while no significant differences were found in the concentrations of thiopental in the different parts of the central nervous system (CNS), fat or muscle tissue. The kinetics of CPX were also affected. The experimental group (CPX + thiopental treated) had significant higher brain concentrations of CPX than the corresponding only CPX treated control group while no differences were found in the serum concentrations of CPX between the groups. As previously suggested, the distribution of thiopental in the CNS is not only dependent on its lipid solubility, but also as a weak organic acid, on the transport system for organic acids out of the CNS which both thiopental and ciprofloxacin seem to use and mutually compete for it.
The Psychopharmacology of 5‐HT3Receptors*
Authors: Costall Brenda , Naylor Robert J.
Published: March 2009

Abstract:5‐HT3receptors have an exclusive neuronal location and evidence is presented of their involvement in behaviour. 5‐HT3receptor antagonists such as ondansetron, tropisetron and zacopride have provided the critical pharmacological tools to reveal a potent and efficacious ability to regulate disturbed behaviour. Thus the 5‐HT3receptor antagonists will restore to normal rodent and primate behaviour disturbed by increasing limbic dopamine function, aversive situations, cognitive impairments and drug abuse. The remarkable feature of their action is a failure to modify normal behaviour. This unique pharmacological signature has ensured a wide interest in the potential role of the 5‐HT3receptor antagonists in the treatment of schizophrenia, anxiety, age related memory impairment and the problems of withdrawal from drugs of abuse. The preclinical data and preliminary clinical observations are presented.
The Antibacterial Effect of Some Neuroleptics on Strains Isolated from Patients with Meningitis
Authors: Mortensen Ida , Kristiansen Jette E. , Christensen A. Vibeke , Hvidberg Eigill F.
Published: March 2009

Abstract:Eighty‐two strains of bacteria (Neisseria meningitidis, Haemophilus influenzae, Enterobacteriaceae, Streptococcus pneumoniae, group B streptococci andListeria monocytogenes) were examined for theirin vitrosusceptibility to eight drugs, seven neuroleptics (perphenazine, fluphenazine, cis(Z)‐clopenthixol, haloperidol, clozapine, clebopride and SCH 23390), and the neuroleptically inactive trans(E)‐clopenthixol. The phenothiazines and the thioxanthenes were, on the whole, the most active drugs when measured, the IC5050for each group of bacteria being 7.4 to 84 mg/1 (with the exception of the activity against the enterobacteriaceae). The antibacterial potency of clozapine, which has an atypical neuroleptic profile, was between 50 and 140 mg/1. Haloperidol also showed an antibacterial activity in the concentration range 35‐140 mg/1. The selective D1antagonist, SCH 23390 and the selective D2antagonist, clebopride, inhibited only few of the bacteria in the concentration range investigated.