bluuebunny/crossref_metadata_2025 huggingface dataset:
Esterases in Schistosomes: Reaction with Substrates and Inhibitors
Authors: Reiner Elsa
Published: July 2010

Studies were made (at 37°, pH 7.6) on the interaction of some organophosphorus compounds and carboxylic acid esters with cholinesterases (EC 3.1.1.7 and EC 3.1.1.8) and A‐esterases (EC 3.1.1.2) in homogenates of Schistosoma mansoni (adults and cercariae) and Schistosoma haematobium (adults). The results are compared with those obtained from the same reactions in other parasitic helminths and in mammalian tissues. Metrifonate (0,0‐dimethyl‐2,2,2‐trichloro‐1‐hydroxyethyl phosphonate) does not seem to react with cholinesterases from parasites or mammals. Dichlorvos (0,0‐dimethyl‐2,2‐dichlorovinyl phosphate) is a phosphorylating inhibitor; the rate constants of inhibition of cholinesterases from schistosomes are in the order of 105 M‐1 min.‐1. Similar or lower rate constants (104 M‐1 min.‐1) are found for cholinesterase inhibition in other parasitic helminths and mammals. S. mansoni and S. haematobium hydrolyse carboxylic acid esters (10 mM) in decreasing order: phenylacetate (about 2 μmol per hour per mg protein), acetylthiocholine, propionylthiocholine, butyrylthiocholine. Dichlorvos (10 mM) is hydrolysed by S. mansoni and S. haematobium at about the same rate as by mammalian erythrocytes and human sera (about 10 μmol per hour per gram wet weight). Neither paraoxon (0,0‐diethyl‐4‐nitrophenyl phosphate) nor methyl‐paraoxon are hydrolysed by S. mansoni and S. haematobium, although both compounds are good substrates for mammalian A‐esterases. The stability of metrifonate and dichlorvos in buffer solutions was also determined (at 37°). Metrifonate is about equally stable in bicarbonate buffer (pH 7.6) and phosphate buffer (pH 7.4) (t1/2=1.5 and 2.6 hrs, respectively), while dichlorvos is considerably more stable in bicarbonate (t1/2 = (36 hrs) than in phosphate buffer (t1/2 = 2.9 hrs).
Levels of Metrifonate and Dichlorvos in Plasma and Erythrocytes during Treatment of Schistosomiasis with Bilarcil®
Authors: Nordgren I. , Bengtsson E. , Holmstedt B. , Pettersson B.‐M.
Published: July 2010

Abstract A method for the simultaneous quantitation of metrifonate (0,0‐dimethyl‐(1‐hydroxy‐2,2,2‐trichloroethyl)‐phosphonate) and dichlorvos (2,2‐dichlorovinyl dimethyl phosphate, DDVP) in human blood has been worked out. It is based upon multiple labelling of the compounds with deuterium and gas phase analysis using the mass spectrometer as a selective detector. The amount of DDVP in plasma is about 1% of the amount of metrifonate. In erythrocytes the corresponding amount of DDVP is 0.5% or less of metrifonate. Both compounds reach peak levels in blood within two hours after oral dosing and are detectable for at least eight hours. Cholinesterase activity in plasma reaches zero levels within 15 min. and remains inhibited for more than eight hours. Red blood cell cholinesterase is inhibited only 60‐80%. According to kinetic calculations, clearance of metrifonate occurs primarily via dichlorvos. If dichlorvos is the only active component, which in all likelihood it is, it's slow release may be important in the schistosomicidal effect. Clinical data in seven metrifonate treated patients revealed that mild vertigo subsiding in a few hours was the most common side effect.
Delayed Neurotoxicity – Do Trichlorphon and/or Dichlorvos Cause Delayed Neuropathy in Man or in Test Animals?
Authors: Johnson M. K.
Published: July 2010

Abstract Many, but not all, reports of delayed neuropathy associated with acute poisoning by trichlorphon refer to cases in U.S.S.R. Adulteration of technical trichlorphon with the ethyl analogue would greatly increase the neurotoxic hazard but analysis of a few samples has not revealed such impurities. Simultaneous ingestion of alcohol does not appear to increase neuropathic hazard. In hens double doses of trichlorphon each exceeding unprotected LD50 can produce moderate neuropathy associated with appropriately high inhibitions of neurotoxic esterase. Similar results are obtained with 2 doses of 10XLD50 of dichlorvos. In vitro the inhibitory power of dichlorvos against neurotoxic esterase of hen brain is 0.02 X the power against acetylcholinesterase. This ratio correlates reasonably with the ratio of LD50/neuropathic dose. The factor for human brain enzymes is 0.06 suggesting that man is more susceptible to neuropathic effects of near‐lethal doses of circulating dichlorvos. It is concluded that the only neuropathic hazard to man from good quality trichlorphon arises from rapid ingestion of massive doses. To obtain critical levels of inhibition of neurotoxic esterase and to cause neuropathy in man by repeated doses would require each dose to be severely toxic. Dichlorvos ingested in large doses is likely to kill rather than to cause neuropathy.
Leucocytic and Haemostatic Reactions of the Indian Catfish, Heteropneustes fossilis, Subjected to Environmental Pollution by Sewage, Fertilisers and Insecticides
Authors: Srivastava Prabodh Narain , Narain Arun Shanker
Published: July 2010

Abstract: Total and differential leucocyte counts, thrombocyte count and blood clotting time of fishes exposed up to 40 days to sewage and some of its individually reproduced chemical factors, fertilisers (urea, potash), chlorinated insecticides (BHC, endrin) and organophosphorus insecticides (monochrotophos, phosphamidon) indicate pathological disturbances involving injury and haemorrhage in tissues.
Effects of SRS (Slow Reacting Substance) on Cyclic Nucleotides in Guinea Pig Tracheal Muscle
Authors: Hedman S. E. , Andersson R. G. G.
Published: July 2010

Abstract: Leukotriene (SRS) appears to contribute to the prolonged phase of the tracheal contraction induced by egg albumin, indomethacin and tartrazine as this response was effectively antagonised by FPL 55712. Egg albumin, indomethacin and tartrazine reduced the cAMP level of guinea pig trachea pretreated with adrenergic, cholinergic, histaminergic and 5‐hydroxytryptaminergic antagonists. Egg albumin, but not the other agents, caused a transient increase of the cGMP content. The metabolic and contractile effects were blocked by FPL 55712. It is suggested that the cAMP reduction caused by egg albumin, indomethacin and tartrazine might promote contractions of the tracheal muscle.
Decreased Schultz‐Dale Reaction in Airways from Sensitized Guinea Pigs Treated with Threshold Concentrations of Egg Albumin in Vivo
Authors: Hedman Susan E. , Andersson Rolf G. G.
Published: July 2010

Abstract: Treatment of egg albumin sensitized guinea pigs with repeated concentrations of egg albumin changed the Schultz‐Dale response. The dose‐response curve of egg albumin on the trachea was shifted to the right. Both the amount of SRS‐A and histamine released by antigen exposure from sensitized or desensitized guinea pig lungs were almost similar. Regarding the number of H1‐receptors in an isolated membrane fraction from the lungs of sensitized and desensitized guinea pigs, no significant differences was observed. On the contrary, the receptor‐response to SRS‐A was found to be decreased in desensitized trachea in comparison with sensitized trachea. The treatment of guinea pigs with repeated threshold concentrations of histamine did not change the contractile response neither to histamine nor to egg albumin. The decreased Schultz‐Dale response after repeated egg albumin treatment in vivo might depend on desensitization of a hypothetical SRS‐A receptor.
General and Local Toxicity of 5‐Hydroxymethyl‐2‐Furfural in Rabbits
Authors: Rasmussen Allan , Hessov Ib , Bojsen‐Møller Marie
Published: July 2010

Abstract: General toxicity (A) and vein damaging properties (B) of 5‐hydroxymethyl‐2‐furfural (HMF) were studied in rabbits. A. 400 mg HMF was given as subcutaneous injections twice a day for a week. It was not possible to demonstrate any harmful effect of the injecitions on the following parameters: weight, haemoglobin, leucocytes, platelets, serum‐protein, serum‐alanine‐aminotransferase, alkaline phosphatase, liver cell necrosis or hepatic steatosis as compared with a control group. B. Addition of 200 mg HMF/l isotonic NaCl solution did not increase the vein irritating effect of the solution, when given as a 5 hours' continuous intravenous infusion. The amounts of HMF used in this study far exceeded what patients receive from glucose solutions.
Peripheral Metabolism of β‐Carboline‐Carboxylic Acid Esters
Authors: Simonsen H. , Nielsen M. , Bræstrup C.
Published: July 2010

Abstract: Esters of β‐carboline‐3‐carboxylic acid have recently been identified as potent inhibitors of brain benzodiazepine receptors in vitro. Ethyl β‐carboline‐3‐carboxylate (β‐CCE), however, is a rather weak inhibitor in vivo of benzodiazepine receptors in mice. The ED50‐value was 91 mg/kg intraperitoneally 35 min. after administration (ED50 is that dose which inhibits by 50% the specific binding of 3H‐flunitrazepam intravenously). ED50 for β‐CCE was 2–20 fold lower in mice pretreated with organophosphorus esterase inhibitors, concomitantly with the observation of strong inhibition of liver and kidney hydrolyzing activity, using 3H‐propyl β‐carboline‐3‐carboxylate as substrate. The rat brain contains only approximately 0.1% of the hydrolyzing activity as compared to the liver. It is concluded that some esters of β‐carboline‐3‐carboxylate exhibit only weak effects on benzodiazepine receptors in living animals due to hydrolysis outside the brain.
Inhibition of Enkephalin Binding to Opiate Receptors by Zinc Ions: Possible Physiological Importance in the Brain
Authors: Stengaard‐Pedersen Kristian
Published: July 2010

Abstract: Zinc ions can totally block stereospecific binding of 3H‐met‐enkephalinamide (2‐D‐ala‐5‐L‐methionine) to opiate receptor sites in synaptic membranes of the hippocampus, the cerebral cortex and the basal ganglia of the rat brain. Analysis of binding isotherms indicates that this inhibitory effect involves a decrease in both receptor affinity and the number of binding sites. Our data also suggest that the zinc ions react with essential SH‐groups of the opiate receptor. The endogenous concentrations of zinc ions in the hippocampus, the cerebral cortex and the basal ganglia are compatible with the concentrations needed to inhibit opiate receptor binding in vitro. Especially the hippocampus contains a high concentration of zinc ions, which are localized exclusively in the giant boutons of the mossy fibers. Further, the hippocampal distribution of enkephalin and zinc ions is identical and confined to the mossy fiber zone. Hence, zinc ions may represent important modulators of opiate receptor binding in the central nervous system, particularly in the hippocampal mossy fiber zone.
Influence of Albumin Concentration in the Foetal Circulation on the Placental Transfer of 2,2′,4,4′,5,5′‐Hexachlorobiphenyl in the Guinea‐pig
Authors: Kihlström Ingemar
Published: July 2010

Abstract: Placental transport of 2,2′,4,4′,5,5′‐hexachlorobiphenyl in the guinea‐pig was studied by means of perfusion technique. This transfer was rapid when heparinized blood was used as perfusion medium. The same concentration of the chlorobiphenyl in both maternal and foetal compartments was achieved about 20 min. after start of infusion. It was also shown that when dextran solution or dextran solution with addition of Intralipid® to the same concentration as the total lipid concentration in blood, were used as perfusion medium, there was no placental transport of the chlorobiphenyl. Furthermore, it was shown that the placental transport of the chlorobiphenyl was strongly dependent on the albumin concentration, but independent of the γ‐globulin concentration in the perfusion medium.
Ethoxyacetic Acid and N‐Ethoxyacetylglycine: Metabolites of Ethoxyethanol (Ethylcellosolve) in Rats
Authors: Jönsson Anna‐Karin , Pedersen Jörgen , Steen Göran
Published: July 2010

Abstract: Ethoxyethanol (ethylcellosolve) was administered to rats by inhalation and by feeding per os. Two metabolites were detected and identified: ethoxyacetic acid and N‐ethoxyacetylglycine. The identity of these metabolites was confirmed by synthesis of N‐ethoxyacetylglycine methyl ester, ethoxyacetic acid being commercially available.
Effects of Repeated Dosing of Methyl Mercury on in Vivo Protein Synthesis in Isolated Neurones
Authors: Syversen Tore L. M.
Published: July 2010

Abstract: Wistar rats were given orally methyl mercury in daily doses for up to 45 days. Animals receiving 5 mg methyl mercury/kg developed weight loss after 20 doses. The neuronal in vivo protein synthesis was affected in both groups given 1 and 5 mg methyl mercury/kg. Weight loss, early toxic signs and a decreased protein synthesis all seem to occur at a cerebellar mercury level between 3–6 μg Hg/g.
Mechanism of Ergotamine‐induced Decrease of Peripheral Systolic Blood Pressure in Man
Authors: Tfelt‐Hansen Peer , Eickhoff Jens H. , Olesen Jes
Published: July 2010

Abstract: We have previously reported a consistent decrease of peripheral‐central systolic blood pressure (SBP) gradients after ergotamine. SBP was measured with cuffs and it is unknown whether measured values reflect changes of intra‐arterial SBP or increase of vessel wall tone beneath the cuffs. We hence studied the effect of ergotamine tartrate 0.5 mg intravenously on finger‐arm systolic gradients after the following procedures: Infiltration around finger arteries with papaverine (n = 2) and dihydralazine (n=3), occlusion of blood supply to a finger by an inflated cuff before and 2 hours after ergotamine (n = 6). A normal reduction in finger‐arm systolic gradients was seen. The ergotamine‐induced decrease of peripheral SBP must therefore be due to a fall in peripheral intra‐arterial SBP i.e. to contraction of arteries proximal to the digital arteries. Intra‐arterial injection of 10 μg ergotamine tartrate caused similar decrease in finger‐arm systolic gradients as intravenous administration of 0.5 mg (n= 1) indicating a peripheral site of action.
The Initial Phase of the Dextran‐induced Anaphylactoid Reaction in the Rat: A Comparison of Inhibitors of the Blood Pressure Fall
Authors: Berstad Jan
Published: July 2010

Abstract: The histamine H2‐receptor antagonist cimetidine (25–100 mg/kg) caused a partial inhibition of the pronounced blood pressure fall induced by dextran (Macrodexå, 40–100 mg/kg) in the rat. The inhibition by cimetidine could not be distinguished from the inhibition achieved by the serotonin D‐receptor antagonist bromolysergic acid diethylamide (BOL, 1–4 mg/kg). Doses of cimetidine and BOL that gave submaximum inhibitory effects separately, showed approximately additive effects when combined. The combined effect of these drugs never exceeded the maximum effects of the drugs separately, whereas injection of tranexamic acid (AMCHA, 100–300 mg/kg) together with cimetidine or BOL, increased the total inhibition. Previous works showed that dextran injected intravenously into rats reduced the level of plasminogen (PG) and plasminogen proactivator (pro‐PGA) in plasma (Briseid et al. 1979; Berstad 1980a; Berstad & Briseid 1982). High doses of AMCHA (200 mg/kg) did not inhibit these effects, but significantly increased the lowering caused by dextran of the capacity of high molecular weight kininogen (HMWK) to function as a cofactor in the activation of factor XII. BOL (1–4 mg/kg, Berstad 1981) and cimetidine (50–100 mg/kg) also reduced the cofactor capacity of HMWK in the doses that were required to provide a manifest inhibition of the dextran‐induced blood pressure fall. It is suggested that the early phase of the state of shock induced by dextran in the rat can be counteracted at different sites, correlated with histamine and serotonin receptors on the one hand, and with an effect antagonized by AMCHA, on the other. The lowest effective doses of cimetidine and BOL were rather high, suggesting a less specific mechanism for their effects than inhibition at selective receptor sites.
Effects of Lesions in the Parafascicular Nucleus on Catecholamine Synthesis and Number of Muscarinic Receptor Binding Sites in the Striatum of the Rat
Authors: Ahlenius S. , Nordberg A.
Published: July 2010

Abstract: Unilateral radio‐frequency lesions of the parafascicular nucleus were performed in rats. Seven days, but not 24 hrs, postoperatively the following effects were observed in the ipsilateral striatum: (A) an increase in dopamine synthesis as estimated by the accumulation of DOPA following inhibition of cerebral aromatic L‐amino acid decarboxylase; (B) an increase in dopamine levels and (C) a decrease in the number of muscarinic receptors binding sites using [3H] QNB as receptor ligand.
Possible Regulatory Role of Histamine in Human Platelet Function Examined by Thrombin‐induced Serotonin Release
Authors: Norn S. , Skov P. Stahl , Hansen K. W. , Klysner R. , Geisler A.
Published: July 2010

Abstract: The influence of histamine on human platelet function was studied by thrombin‐induced serotonin release. The thrombin‐induced 3H‐serotonin release was confirmed to be a rapid process which does not require external calcium. Histamine was found to reduce the release of serotonin and the inhibition was abolished when H1‐plus H2‐antagonists were added together with histamine. H1‐ and H2‐receptor stimulation was examined in two ways, by a combination of histamine with cimetidine or diphenhydramine and by the selective agonists 2‐(2‐pyridyl)‐ethylamine and impromidine. In both instances H1‐ and H2‐stimulation was found to reduce the platelet serotonin release. These results suggest a regulatory role of histamine in the platelet function by stimulation of platelet H1‐ and H2‐receptors.
Systemic Availability of Acetylsalicylic Acid in Human Subjects after Oral Ingestion of Three Different Formulations
Authors: Petersen Thor , Husted Steen E. , Pedersen Anders Kirstein , Geday Erling
Published: July 2010

Abstract: Systemic availability of acetylsalicylic acid (ASA) in normal human subjects after oral ingestion of 1 g in three different formulations was determined by using high‐pressure liquid chromatography for ASA assay. For an effervescent, a plain and a sustained release preparation systemic availabilities expressed in percent of the ingested dose were 16.9±3.2, 8.6±1.2 and 2.6±0.4%, respectively. All subjects had clearly measureable amounts of ASA in plasma after oral intake of a sustained release preparation with an average peak concentration of 15 μmol/1. Peak concentration after an effervescent and plain formulation was on the average 80 and 40 μmol/1, respectively. Half‐life of ASA in plasma was 18.1±1.2 min. for the effervescent and 28.7±5.3 min. for the plain preparation, while the elimination phase was too ill defined for the sustained release formulation. Average plasma half‐life of salicylic acid (SA) was similar after the three different administration forms with values between 3.0 and 3.7 hrs. Further, no difference in SA distribution volumes or amounts of SA absorbed was found. The present study demonstrates that oral ingestion of ASA in effervescent, plain and sustained release formulations gives rise to significant amounts of ASA in plasma. Concentrations found indicate that long‐term antithrombotic therapy with ASA in a sustained release formulation may be possible.
Metabolism of Progesterone by the Nasal Mucosa in Mice and Rats
Authors: Brittebo Eva B.
Published: July 2010

Abstract: The metabolism of 4‐14C‐progesterone by the nasal mucosa and lung from mice and rats was investigated in vitro. Using thin‐layer radiochromatography at least 10 and 7, yet unidentified, metabolites were found at incubation with slices from the nasal mucosa and lung, respectively. The results further indicated that the rate of progesterone metabolism was higher in the nasal mucosa than in the lung. Autoradiography of lung slices incubated with 14C‐progesterone showed that a selective localization of radioactivity occurred in the bronchial mucosa.
Effects of Methyl Mercury and Triethyllead on Na+K+ATPase and Pyruvate Dehydrogenase Activities in Glioma C6 Cells
Authors: Grundt I. K. , Roux F. , Treiclh I. , Loriette C. , Raulin J. , Fournier E.
Published: July 2010

Abstract: The effect of methyl mercury (MeHg) and triethyllead (Et3Pb) on the membrane bound SH‐enzymes Na+K+ATPase and pyruvate dehydrogenase (PDH) was studied in relation to the effect on the galactosyl ceramide sulfotransferase (CST) and to morphological changes in glioma C6 cells. Two‐day‐old cultures were incubated for 1 or 20 hrs with 5–30 μg MeHgCl and 2–8 μg Et3PbCl/mg cell protein. The results show that both compounds induced morphological changes and a reduction of CST activity at growth inhibitory concentrations. A less marked reduction of Na+K+ATPase was induced with increasing exposure time only in MeHgCl treated cultures, and PDH activity was not affected by either of the compounds under the experimental conditions. Thus, an interference with Na+K+ATPase and PDH activities do not appear to be a primary effect of MeHg and Et3Pb intoxication.
The Effect of Cadmium and Manganese on the Distribution of Iron‐59 in Partially‐hepatectomized Rats
Authors: Srivastava R. C. , Kaur G. , Srivastava R. , Dwivedi R. S.
Published: July 2010

Abstract: The distribution of iron‐59 in blood at various time intervals was studied in sham and partially‐hepatectomized rats after a single intravenous injection of 59Fe (III) citrate. A significant difference was observed in the rate of disappearance and reappearance of iron‐59 in circulation. Administration of cadmium and manganese at a concentration of 0.5 and 2 mg/kgb.wt., respectively, did not cause any significant change in this pattern. A significant decrease in iron‐59 incorporation in the liver of hepatectomized rat was produced by cadmium while manganese had no effect.
Adenylate Cyclase in Rat Synaptosomal Plasma Membranes and Caudate Nucleus Homogenate: Effects of Dopamine, E Prostaglandins, Guanyl‐5′‐yl‐imidodiphosphate and Morphine
Authors: Grynne Birthe H.
Published: July 2010

Abstract: The adenylate cyclase in two particulate preparations from rat brain, a homogenate from caudate nucleus (CN‐homogenate) and a synaptosomal plasma membrane fraction (SPM‐fraction) from whole rat brain was investigated. Stimulation of the enzyme by dopamine and prostaglandins E1 and E2 was found in the CN‐homogenate while only a weak prostaglandin E1 and E2 stimulation and no dopamine stimulation could be found in the SPM‐fraction. Guanyl‐5′‐yl‐imidophosphate (GppNHp) and NaF could stimulate the adenylate cyclase in both preparations. Morphine up to 10–5 M altered neither the basal enzyme activity nor any of the stimulated enzyme activities.
Subacute Toxicity of Vinyltoluene Vapour: Effects on the Hepatic and Renal Drug Biotransformation and the Urinary Excretion of Thioether
Authors: Heinonen Tuula , Nickels Juha , Vainio Harri
Published: July 2010

Abstract: Male rats were exposed by inhalation to vinyltoluene at concentrations of 50, 100, or 300 p.p.m. for 8. 12 or 15 weeks. Vinyltoluene was found to be metabolized to glutathione conjugates via the formation of electrophilic intermediates. This metabolic pathway was suggested by the decreased hepatic non‐protein sulfhydryl content, with a concomitant increase in the urinary excretion of thioethers. The excretion of thioethers showed no saturation phenomena, suggesting that the formation of electrophilic intermediates capable of conjugating with glutathione is fairly linear, at least with exposure to vinyltoluene vapour up to 300 p.p.m. The slight increase in the activities of hepatic drug biotransformation enzymes (7‐ethoxycoumarin 0‐deethylase, UDPglucuronosyltransferase) observed after 8 weeks of exposure to vinyltoluene vapour disappeared by week 15 irrespective of the continued intermittent inhalation of vinyltoluene. Histological study revealed that cell size had decreased in the rats exposed to vinyltoluene.
The Effects of Fluoride on Cell Growth of Two Human Cell Lines and on DNA and Protein Synthesis in HeLa Cells
Authors: Imai Toshio , Niwa Motoo , Ueda Masahiro
Published: July 2010

Abstract: The effect of sodium fluoride on the growth of two continuous human cell lines, i.e. HeLa cells and human conjunctiva clone 1–5C‐4 cells, was studied. The growth of HeLa cells and clone 1–5C‐4 cells was arrested nearly completely by the addition of 0.95 and 1,90 mM of sodium fluoride, respectively. DNA synthesis in HeLa cells, determined by incorporation of 3H‐thymidine, was not affected appreciably for the first 24‐hr period after the addition of sodium fluoride. Markedly reduced incorporation, however, occurred during the next 24‐hr period. Thus, there was a discrepancy between the immediate cessation of cell division and the delayed suppression of DNA synthesis. On the other hand, a suppressive effect of sodium fluoride on protein synthesis determined by 14C‐leucine incorporation was evident already during the first 24‐hr period. The results indicate that the inhibition of protein synthesis is the main cause of growth inhibition.
Preclinical Studies on Human Insulin. I. Acute and Subacute Toxicity Studies
Authors: Gamst‐Andersen H. , Hjortkjær R. K. , Lorenzen F. Hjort , Ashby R.
Published: July 2010

Abstract: Human insulin (prepared from porcine insulin) and porcine insulin were tested for acute toxicity by subcutaneous administration to unfasted mice and rats and fasted mice. The animals were observed for signs of reaction and post mortem examination was performed. LD50 values were calculated when possible. The LD50 values in the unfasted animals were several times higher than in the fasted mice, but similar for the two insulin preparations. The deaths and the signs observed were most probably caused by hypoglycaemia. No dose‐related macroscopic organ changes were found. In a 28 day toxicity study rats were given human or porcine insulin subcutaneously at dosages of 2, 20 or 200 U/kg/day. The criteria examined included mortality, body‐weight change, food consumption and utilization, haematology, blood chemistry, urinalysis, opthalmoscopy, organ weights, gross‐ and histopathology. A few deaths occurred because of hypoglycaemia. In surviving rats from dosage groups 20 and 200 U/kg/day of either insulin preparation higher plasma glucose levels than in the control were observed 24 hours after dosing. Higher food intake and body‐weight gains, lower plasma protein concentrations and higher urinary volumes with associated low specific gravity were observed in animals given either human or porcine insulin at 200 U/kg/day. No other adverse effects were registered, and no overt difference was found between the effect of human and porcine insulin.
Release and Inhibition of Uptake of 5‐Hydroxytryptamine in Blood Platelets in Vitro by Copper and Methyl Mercury
Authors: Tuomisto Jouko , Komulainen Hannu
Published: July 2010

Abstract: Divalent copper (Cu) and methyl mercury (Met‐Hg) are potent inhibitors of the uptake of 5‐hydroxytryptamine (5‐HT) in rat hypothalamic synaptosomes in vitro. To assess the usefulness of blood platelets as a peripheral model of central serotonergic nerve endings for neurotoxicological studies, for comparison human and rabbit platelets were utilized. Cu inhibited 5‐HT uptake into human platelets when platelets were separated from plasma (the ICSO 0.7–0.8 μM). Plasma added with platelets abolished the toxic influence of Cu towards platelets. Met‐Hg inhibited 5‐HT uptake both in washed platelets (the IC50 0.2 μM) and in platelets added in plasma (the IC50s 10–15 μM). The inhibition of uptake by Met‐Hg did not depend on buffer Ca and Mg. At low concentrations of Cu, the uptake tended to be more inhibited in the presence of Ca and Mg. Zn and Hg did not affect 5‐HT uptake up to 100 μM. Pb inhibited it transiently (28 % at 1 μM) in the presence of Ca and Mg. Met‐Hg induced the release of endogenous 5‐HT from rabbit platelets when they were in a suspension in Ca‐free buffer, but Cu did not, even at 100 μM concentration. The results suggest firstly, that blood platelets give results comparable with brain synaptosomes regarding inhibitory effects of metals on 5‐HT uptake provided plasma is decanted. Secondly, the inhibition of 5‐HT uptake by Cu appears to be purely plasma membrane related but Met‐Hg may, in addition, induce release of 5‐HT from storage granules.
Sustained Effect of Zinc‐protamin‐glucagon in Hyperlipidaemic Patients
Authors: Buch Jan , Buch Annette
Published: July 2010

Abstract: Is is well known from laboratory investigations and acute intervention studies that glucagon is involved in lipid metabolism. The present study was undertaken in order to evaluate a possible sustained effect of zinc‐protamin‐glucagon in moderately hyperlipidaemic patients. 4 patients were investigated after an acute bolus dose of glucagon 5 mg intravenously and 16 patients were given zinc‐protamin‐glucagon 5 mg subcutaneously, b.i.d. for 5 days. A similar degree of decrease of plasma cholesterol and triglycerides was obtained in the acute and chronic study, while the increase in fasting blood sugar and plasma insulin seen in the acute study was not present after 5 days treatment. The effect on plasma triglycerides was much more variable than the effect on plasma cholesterol. Five days after treatment the lipid concentrations had returned to the pretreatment values. The effect could not be predicted from the pretreatment lipid concentrations, neither by the type of hyperlipidaemia present. The decrease in plasma cholesterol and triglycerides were not correlated. The drug might prove useful in the long term research of lipid metabolism and the various complex hormonal interactions.
Cardiovascular Effects of Zimelidine and Tricyclic Antidepressants in Conscious Rats *
Authors: Forsberg Tomas , Lindbom Lars‐Olof
Published: July 2010

Abstract: Blood pressure, heart rate and electrocardiograms were recorded in conscious rats during intravenous injections of consecutively increasing doses of zimelidine, amitriptyline, clomipramine, desipramine and imipramine. The tricyclic antidepressants (TCA's) increased blood pressure from low doses and induced shortlasting decreases in blood pressure at higher doses. Heart rate was initially increased by amitriptyline while the other TCA's tended to decrease heart rate dose‐dependently. The TCA's prolonged the QRS and QT intervals dose‐dependently from low doses and the PR interval from intermediate doses. Zimelidine did not affect blood pressure or heart rate until high doses were given. The PR interval was not affected by zimelidine. Moderate to high doses of zimelidine prolonged the QT length and high doses widened the QRS complex. The results indicate a good cardiovascular tolerance for zimelidine.
No Effect of Prolonged Fluoride Exposure on Cytochrome P‐450 and Associated Monooxygenases or on the Level of Polyamines in the Rat
Authors: Hongslo Jan K. , Holme Jørn , Hongslo Cecilie F. , Eliassen Knut A. , Dybing Erik , Holland Roy I. , Ekstrand Jan
Published: July 2010

Abstract: When exposing rats to drinking water containing 100 p.p.m. fluoride for 8 weeks, no effect could be detected in biochemical parameters of the liver, such as the concentrations of the polyamines putrescine, spermidine and spermine; the levels of microsomal protein and cytochrome P‐450; or the activities of two associated monooxygenases, aryl hydrocarbon hydroxylase and ethylmorphine N‐demethylase. Neither was there any increase in plasma glutamic‐oxalacetic transaminase indicative of liver damage.
Differential Effects of Insulin on Brain Monoamine Metabolism in Rats
Authors: Berggren Ulf , Engel Jörgen , Liljequist Sture
Published: July 2010

Abstract: The effect of a subconvulsive dose of insulin, which caused a 70% reduction of plasma glucose levels, on catecholamine and 5‐hydroxytryptamine turnover in different brain regions of rats was investigated. The turnover of norepinephrine was found to be increased in the hemispheres and that of 5‐hydroxytryptamine was increased in the limbic forebrain and hemispheres, whereas the dopamine turnover was decreased in the striatum and limbic forebrain.
Effects of Quinuronium Sulfate Pre‐exposure on Hepatic Excretion of Sulfobromophtalein (BSP) as Measured by Isolated Perfused Rat Liver
Authors: Mitema Eric S. , Nafstad I. , Freslie A.
Published: July 2010

Abstract: Effects of quinuronium sulphate pre‐exposure on hepatic excretion of sulfobromophthalein (BSP) as measured by isolated perfused rat liver was investigated. Seventeen rats were used in the study. Rats were divided into controls (Group 1, n = 5), low quinuronium treated animals (Group 2, n = 6), and high quinuronium treated animals (Group 3, n = 6) receiving 0, 1.5 or 2.3 mg quinuronium sulphate/kg intraperitoneally, respectively. Each animal was dosed 30 min. before sacrifice. After 30 min. of equilibrium perfusion, BSP was introduced and the experiment continued for 2 hours. Perfusate and bile were collected at designated time intervals and the volume of bile was noted. BSP in perfusate and bile was assayed. Half‐life in minutes (t1/2$pLS.E.) of BSP disappearance from perfusate in groups 1, 2 and 3 were 12.5$pL1.8, 13.7$pL1.0 and 16.8$pL3.3, respectively. Group 2 and 3 rats had a significant decrease of BSP excretion in bile (P<0.01) compared to group 1 rats. Bile volumes decreased in both quinuronium pre‐exposed groups of rats compared to control rats. These observations indicate that quinuronium affects liver function.
Arrhythmogenic Assessment of Prenalterol in Conscious Dogs
Authors: Aberg Gunnar , Jannou Gilbert , Meeker Jeff , Olson Richard , Persson Bengt‐Arne , Povalski Henry
Published: July 2010

Abstract: Possible arrhythmogenic side‐effects of the positive inotropic agent prenalterol were studied in conscious dogs, three to four days after coronary artery ligation. Prenalterol showed a propensity to cause arrhythmias in one out of eight dogs, thereby confirming published data from clinical studies.
Today's Requirements in Food, Drug and Chemical Control.
Authors: Osterberg R.E.
Published: July 2010

Abstract The acute toxicity tests which generate LD50's or LC 50's have been used for several decades to detect potential acute hazards to humans who are exposed to toxic substances. Several federal regulatory agencies use the results of these tests in regulating chemicals such as food additives, drugs, products found in homes such as pesticides and household cleaners, chemicals produced in industrial environments and chemicals which are transported in interstate commerce.

Acute toxicity data are used by these federal agencies in many different ways depending upon their regulatory missions and the regulations that these agencies utilize to accomplish their missions. For instance, the Federal Hazardous Substances Act regulations used by the Consumer Product Safety Commission address the specific labeling of consumer products dependent upon the calculated oral or dermal LD50. In some instances, a consumer product can be banned from commerce as an imminent hazard dependent upon the peculiar toxicity of the product.

However, the Food and Drug Administration with the authority contained in the Federal Food, Drug and Cosmetic Act uses acute toxicity data in determining the approvability of intentional food additives and indirect food additives contained in food packaging. In addition, such data are used to provide guidance for the design of longer term studies in man and animal needed to obtain food and drug approvals.

Since many federal regulatory agencies require acute toxicity tests in some phase of their regulatory activities, it was decided to develop common guidelines for these tests. As a result, the Interagency Regulatory Liaison Group (IRLG) was established in 1977, in part to develop guidelines to resolve existing test protocols and to design tests to be used by all IRLG agencies for chemical testing.

In mid 1979, a draft acute oral toxicity protocol for rodents was released for general public comment. As a result of this action, the guidelines were modified to incorporate some of the expressed public ideas. One modification provided for the use of a limit test involving 10 rats dosed at a level of 5g/kg which could preclude the use of further numbers of animals. If no compound related mortality was observed at this dose, the compound would be considered as non‐toxic. The acute toxicity guidelines were finalized and published in January, 1981.

Although the IRLG recognizes that at present the acute toxicity rodent test is the most reliable method to determine potential acute hazards to man, it also recognizes that alternatives such as in vitro tests may prove useful once further research and development refine them to the point of regulatory utility.
Inhibition by Low Molecular Weight Dextran of the Blood Pressure Fall and the Lowering of Plasminogen Proactivator Induced by Clinical Dextran in the Rat
Authors: Briseid Gudrun , Briseid Kjell
Published: July 2010

Abstract: The intravenous injection into rats of dextran with a molecular weight of 1,000 (LMr dextran) in doses 200 mg/kg induced rapid, but transient falls in blood pressure. Pretreatment of the rats with LMr dextran 200 mg/kg caused a partial inhibition of the profound blood pressure fall induced by the injection of clinical dextran with a molecular weight of 70,000 (HMr dextran), 40 mg/kg. In accordance with previous works (Briseid & Berstad 1981; Berstad & Briseid 1982; Berstad 1982) it was found that the intravenous injection of HMr dextran lowered the plasma levels of plasminogen proactivator (pro‐PGA) and functionally active high molecular weight kininogen (HMrK). Also LMr dextran, 200 mg/kg, induced significant reductions in the mentioned parameters, but less extensive than those obtained by HMr dextran, 40 mg/kg, and pretreatment of the rats with LMr dextran inhibited the subsequent effects of HMr dextran. It is suggested that a dextran‐activated plasminogen activator might be an early link in the mechanism underlying the dextran‐induced state of shock in the rat.
Distribution and Excretion of a New Insect Repellent, 14C‐DEM, in the Mouse after Intravenous, Cutaneous, and Oral Administration
Authors: Thorsell Walborg , Blomquist Lars , Appelgren Lars‐Erik
Published: July 2010

Abstract: The distribution of 14C after administration of 14C‐DEM was qualitatively similar irrespective of the administration route (intravenous, cutaneous or oral). The major accumulation sites were lacrimal and nasal glands, parotis, liver, and kidney. The main excretion was through the urine and only minor quantities through the faeces and the expired gases. It could be confirmed that the new repellent had a low skin uptake.
Effect of Interaction of Heavy Metals on (Na+‐K+) ATPase and the Uptake of 3H‐DA and 3H‐NA in Rat Brain Synaptosomes
Authors: Chandra Satya V. , Murthy R. C. , Husain Tahir , Bansal S. K.
Published: July 2010

Abstract: The effect of interaction of Mn2+, Pb2+ and Cd2+ on (Na+‐K+) ATPase and uptake of labelled dopamine (3H‐DA) and labelled noradrenaline (3H‐NA) were studied in vitro in rat brain synaptosomes. The inhibition of (Na+‐K+) ATPase by Pb2+ and Cd2+ alone was concentration dependent, however, Mn2+ had almost no effect on the activity of this enzyme. Interaction of Cd2+ with either Pb2+ or Mn2+ was most powerful in inhibiting the activity of synaptosomal transport ATPase. Lower concentrations of Pb2+ increased while higher concentrations inhibited synaptosomal uptake of 3H‐DA and 3H‐NA. Lower concentrations of Cd2+ increased the uptake of 3H‐DA while at concentrations of 100 μM, the uptake was inhibited, this metal had strong inhibitory effect on the uptake of 3H‐NA. Mn2+ had inhibited the uptake of labelled amines. Interaction of Mn2+ with Pb2+ or Cd2+ produced inhibition on the uptake of 3H‐DA and 3H‐NA. The results of the uptake of biogenic amines in the presence of metal ions apparently had no correlation with the activity of (Na+‐K+) ATPase which is involved in the active transport of cations across cell membranes.
Nature of 54Mn Binding Protein in Rat Brain, Liver and Serum
Authors: Kalia Kiran , Chandra Satya V. , Viswanathan P. N.
Published: July 2010

Abstract: Studies were undertaken to investigate the 54Mn binding protein in rat serum, liver and brain. Equilibrium dialysis pattern in three biological media with 54Mn against distilled water showed a rectangular hyperbola after 24 hr dialysis. 54Mn in the bag was in the non‐dialysable form, presumably bound to protein. Gel filtration studies with !4Mn bound protein showed that 54Mn had a specific carrier protein, which was identical for all the three biological media tested. The electrophorogram of concentrated 54Mn protein with Comassie blue stain for protein and PAS stain for glycoprotein showed a single band with an equal RF value clearly indicating the glycoprotein nature of 54Mn binding protein. Sulphydryl groups were absent and it had molecular weight of 6.3 x 104 dalton.
Disposition of some Sulphur‐containing Hexachlorobenzene (HCB) Metabolites: Affinity of Methylsulphonylpentachlorobenzene for the Gray Matter of Brain, the Lungs and the Adrenal Zona reticularis **
Authors: Brandt Ingvar , Mohammed Abdulmalik , Lydéen Annika , Slanina Premysl
Published: July 2010

Abstract: The distribution of methylsulphonyrpentachloro‐[14C]benzene (I), methylthiopentachloro‐[14C]ben‐zene (II), 1,4‐bis(methylthio)tetrachloro‐[14C]benzene (III) and 1,2,4‐tris(methylthio)trichloro[14C]benzene (IV) was studied after intravenous injection in mice. The administration of I resulted in a rapid and selective accumulation of radioactivity in the gray matter of the brain, the lung and the zona reticularis of the adrenal cortex. In mice pretreated with metyrapone, or with a high dose of unlabelled I, the radioactivity in the tissues was increased, whereas pretreatment with diethyl maleate did not change the disposition of I. In mice injected with II–IV no site of selective accumulation in the tissues was observed. Similarly to I, compounds II–IV were rapidly excreted in bile/faeces and urine. It is proposed that the sulphone group is essential for the high affinity of I for the brain, lung and adrenal cortex.:
Reduced Cofactor Function of Human High Molecular Weight Kininogen Induced by Human Plasma Kallikrein
Authors: Johansen Harald Thidemann , Briseid Kjell
Published: July 2010

Abstract: Most reports in the literature state that human plasma kallikrein does not destroy the capacity of human high molecular weight kininogen (HMrK) to function as a cofactor in the contact phase activation of factor XII. In the present work preparations of highly purified human plasma kallikrein that showed high plasminogen activator (PGA) activities rapidly reduced the cofactor function of human HMrK. Gel electrophoresis with SDS without reduction showed that all kallikrein preparations tested contained two protein bands, one major band with a Mr of about 83,000, and one weak band with a Mr of 80,000. The main band is probably identical with kallikrein I, which Levison & Tomalin (1982b), using Ac‐Pro‐Phe‐Arg‐OMe‐HCl as substrate, found to be ten times more active (in terms of kcat/Km) than kallikrein II with Mr 3000 daltons lower. The rate of HMrK destruction in our experiments varied with the kallikrein preparation used, but assays of their hydrolytic activities against benzoyl arginine ethylester (BAEe) or the plasma kallikrein selective tripeptide substrate H‐D‐Pro‐Phe‐Arg‐pNA (S‐2302) did not discriminate between enzyme preparations with different HMrK‐destroying capacities. Assay of PGA activities demonstrated a correlation between the level of PGA measured, and the HMrK‐destroying capacity.
7V‐Acetylpenicillamine Potentiated Excretion of Methyl Mercury in Rat Bile: Influence of S‐Methylcysteine
Authors: Refsvik Tor
Published: July 2010

Abstract: N‐acetylpenicillamine, 5 mmol/kg body weight increased biliary excretion of methyl mercury more than three fold. Upon simultaneous administration of the same dose of N‐acetylpenicillamine and 2,5 mmol/kg body weight of S‐methylcysteine biliary excretion of methyl mercury increased only 1.5 fold. In both cases biliary sulfhydryl concentration increased to the same extent, about 5 fold. Decreased biliary excretion of methyl mercury, as a result of liver depletion of reduced glutathione by cyclohexene oxide, could be restored by N‐acetylpenicillamine. This restoration could be depressed by S‐methylcysteine. The experiments undertaken indicate that N‐acetylpenicillamine potentiated methyl mercury excretion occurs by a glutathione S‐transferase dependent mechanism. Bile, collected after successive administration of methyl mercuric chloride, cyclohexene oxide, S‐methylcysteine and N‐acetylpenicillamine contained the methyl mercuric derivatives of N‐acetylpenicillamine and glutathione together with other methyl mercury carrying components not present in control bile. Whether these components play any role in the mechanism of N‐acetylpenicillamine potentiated methyl mercury excretion cannot be stated from the present investigation.
Structural and Functional Impairment of Mitochondria from Rat Livers Chronically Injured by Thioacetamide
Authors: Möller B. , Dargel R.
Published: July 2010

Abstract: The effect of prolonged application of thioacetamide (TAA) on structural and functional properties of isolated liver mitochondria from rats was studied. Mitochondria prepared either from micronodularly cirrhotic livers (TAA application for 3 months) or from macronodularly cirrhotic ones (TAA application for 6 months) exhibited loss of respiratory control due to increased state 4 respiration and decreased state 3 respiration. The mitochondrial content of cytochromes aa3 and b was lowered only after 6 months exposure to TAA. The Mg2+ content of mitochondria from micronodularly cirrhotic livers was reduced to 50%. Mitochondria isolated from rats chronically treated with TAA exhibited lowered Ca2+ uptake rates and a decreased Ca2+ retention time. The analysis of mitochondrial phospholipid fatty acids revealed marked alterations in phosphatidylcholine and cardiolipin leading to a decreased 20:4/18:2 ratio. The functional and structural alterations of the liver mitochondria from chronically treated rats remained unaffected for at least 2 weeks after cessation of TAA application.
Biochemical Pattern in Experimental Exposure of Humans to White Spirit. II. The Effects of Repetitive Exposures
Authors: Pedersen Lisbet Milling , Cohr Karl‐Heinz
Published: July 2010

Abstract: The concentration of P‐immunoglobulins (P‐IgG, P‐IgA, P‐IgM), P‐orosomucoid, S‐creatine kinase (S‐CK), and S‐follicle stimulating hormone (S‐FSH) was investigated in seven subjects exposed to 100 p.p.m. white spirit, 6 hrs daily during 5 days while 5 subjects were used as unexposed controls. The mean values for S‐CK concentration in the exposed group increased significantly with 59% and 76% above the base‐line (0‐hr value) 96 hrs and 168 hrs, respectively, after the start of the exposure (P<0.05), while the mean values for S‐FSH concentration decreased significantly to 11 % and 9% below the base‐line after 24 hrs and 96 hrs (P<0.05), respectively. S‐CK concentration and S‐FSH concentration in the control group remained unchanged. A marked interindividual and intraindividual variance in S‐CK concentration and S‐FSH concentration was observed. No changes in the concentration of immunoglobulins and orosomucoid were observed in both groups during the experiment. The mechanisms for the changes are at present only speculative, but solvent induced changes in muscle cell membranes with subsequent enzyme leakage seem the most reasonable explanation for the increase in S‐CK concentration, while an effect on the hypothalamic FSH releasing hormone may explain the decrease in S‐FSH concentration.