bluuebunny/crossref_metadata_2025 huggingface dataset:
The Distribution and Metabolism of 14C‐Labelled Tamoxifen in Spayed Female Mice
Authors: Wilking N. , Appelgren L.‐E. , Carlström K. , Pousette Å. , Theve N. O.
Published: July 2010

Abstract: The distribution and metabolism of 14C‐tamoxifen (a non‐steroidal triaryl ethylene anti‐oestrogen) have been investigated in ovarieectomized mice. The autoradiograms showed accumulation of radioactivity in the liver and the bile as an indication of an excretory pathway, but a rapid and high accumulation was also seen in the lung and the adrenals, organs normally not considered as target organs for tamoxifen. The liver and sebaceous glands could be detected on the autoradiograms up to fourteen days after a single intravenous dose. However, in most organs the amount of retained radioactivity was very low after 24 hours. By using the autoradiograms as a guideline a metabolic study was performed. High concentrations of unmetabolized tamoxifen was detected in the lung and the adrenals as well as in the pancreas. Relatively high amounts of a compound tentatively identified as 4‐hydroxy‐tamoxifen were present in the pancreas and the liver and there were also indications for the presence of N‐desmethyl‐tamoxifen in these tissues. These metabolites are considered to possess anti‐oestrogenic activity.
Application of Radioreceptor Assay of Benzodiazepines for Toxicology
Authors: Aaltonen L. , Scheinin M.
Published: July 2010

Abstract: A radioreceptor assay (RRA) for determining benzodiazepines (BZ) has been developed and applied to toxicological analysis of serum samples from 21 patients with acute BZ overdosage. The method was sensitive (e.g., lorazepam 17 nM, diazepam 41 nM), and specific for pharmacologically active BZ derivatives. The reproducibility of the results was good (intra‐assay variation <8%, inter‐assay variation <10%). Concentrations measured by the RRA showed a good correlation with those obtained by gas‐liquid chromatographic analysis of the same samples. The quantitative results represent the sum of one or several parent substances and all biologically active metabolites, in proportion to their receptor binding affinities.
Interindividual Variation in Benzo(a)pyrene Metabolism and Composition of Isoenzymes of Cytochrome P‐450 as Revealed by SDS‐Gel Electrophoresis of Human Liver Microsomal Fractions
Authors: Ekström Gunilla , von Bahr Christer , Glaumann Hans , Ingelman‐Sundberg Magnus
Published: July 2010

Abstract:Human liver microsomal fractions from 13 different individuals were characterized with respect to SDS‐polyacrylamide gel electrophoretic profiles and regiospecificity in the metabolism of the polyaromatic hydrocarbon benzo(a)pyrene. Pronounced interindividual differences in the composition of microsomal proteins in the molecular weight region of Mr = 49,000–60,000 were found. Furthermore, gel electrophoresis combined with staining for peroxidase activity indicated most of the variations among the profiles of microsomal proteins being attributed to interindividual differences in the composition of isoenzymes of cytochrome P‐450. One type of human liver microsomal fraction was selectively induced in specimens obtained from patients with known regular drug intake before death and correlated well in molecular weight to the phenobarbital‐inducible form of cytochrome P‐450 in the rabbit. Large variations among the human liver microsomal samples were also seen in the benzo (a)pyrene metabolism. The results indicate the presence of 7–8 different forms of cytochrome P‐450 in human liver microsomes and that the interindividual variations seen in drug metabolism may at least in part be explained by interindividual variations in the distribution of these isoenzymes.
Reduction of Blood Cholinesterase Activities following Administration of Soman by Different Routes in Guinea‐pig
Authors: Sterri Sigrun H. , Kloster Øyvind , Valdal Gunnar
Published: July 2010

Abstract: The inhibition of erythrocyte acetylcholinesterase activity following intravenous, intraperitoneal, subcutaneous, or percutaneous administration of sublethal doses of soman in guinea‐pig has been investigated. The inhibition was found to be almost completed within 1 min., 20 min., 60 min. or 90–120 min. respectively, the inhibition rates were of first order, and half‐lives were dose dependent. The possibility of storage of soman after administration of sublethal doses was also examined by the injection of electric eel acetylcholinesterase. It is concluded that there is very little, if any, storage of free soman in the organism after injection of sublethal doses of soman.
Effect of Alcoholic Beverages on the Pharmacokinetics of Doxycycline in Man
Authors: Mattila M. J. , Laisi U. , Linnoila M. , Salonen R.
Published: July 2010

Abstract: In a randomized cross‐over trial on six healthy medical students, alcohol (lg/kg) ingested as whisky did not modify significantly the absorption of 200 mg of doxycycline (DC) given in two tablets. Cheap red wine with a clear taste of acetic acid postponed the absorption of DC for 2–3 hours without affecting its 24‐hour AUC or urinary excretion significantly. Another similar trial with other wines on 8 healthy students suggested that good regular wines do not retard DC absorption irrespective of their tannic acid content. However, acetic acid may postpone DC absorption by possibly slowing the rate of gastric emptying.
Dose Dependent Induction of Rat Liver Microsomal Cytochrome P‐450 and Microsomal Enzymatic Activities after Inhalation of Toluene and Dichloromethane
Authors: Toftgård Rune , Nilsen Odd G. , Gustafsson Jan‐Åke
Published: July 2010

Abstract:Sprague‐Dawley rats were exposed, by inhalation, to toluene and dichloromethane (500, 1,500 or 3,000 p.p.m.) and to benzene (1,500 p.p.m.) for three days. Toluene and benzene increased the concentration of liver microsomal cytochrome P‐450. A dose dependent increase in thein vitroliver microsomal formation of several metabolites of biphenyl and benzo(a)pyrene was observed for both dichloromethane and toluene. At the highest dose‐level the increase in thein vitroformation of benzo(a)pyrene‐7,8‐dihydrodiol was more than threefold for both dichloromethane and toluene whereas the formation of benzo(a)pyrene‐4,5‐dihydrodiol increased more than five‐fold following exposure to toluene but less than two‐fold after exposure to dichloromethane. Our results suggest that dichloromethane and toluene can modify the metabolism and thereby the toxicity of other environmental contaminants.
The Effect of Zearalenone on Growth Rate, Organ Weight and Muscle Fibre Composition in Growing Rats
Authors: Kiessling Karl‐Heinz
Published: July 2010

Abstract: The effect of prolonged zearalenone administration to growing rats on body and organ weight as well as on muscle fibre composition has been studied. Two muscles, M. longissimus dorsi and M. vastus lateralis. were selected for fibre analyses, and the different fibre types were identified by histochemical staining. Zearalenone caused retarded growth and reduced carcass weight in both sexes. With low daily doses female growth was retarded more than male growth, with higher doses the effect was the opposite. The most evident effects of zearalenone treatment on organ weight were enlargement of the liver in both sexes and of adrenal glands and the spleen in males. No effects were found on heart, kidney, testes or uterus. No significant changes of fibre number or diameter occurred in male rats after prolonged zearalenone feeding. In female rats, however, there was a 40% decrease in the number of αR fibres in vastus and a corresponding increase of αW fibres. Simultaneously the αR fibre size increased with 25%. No significant changes could be found in the activity of two enzymes in vastus, cytochrome oxidase and lactate dehydrogenase, as a consequence of the zearalenone treatment.
Protein Binding of Doxepin and Desmethyldoxepin
Authors: Virtanen R. , Iisalo E. , Irjala K.
Published: July 2010

Abstract: The protein binding of doxepin (DOX) and desmethyldoxepin (DDOX) were studied in serum and plasma samples from healthy volunteers and psychiatric patients. Binding was measured by equilibrium dialysis (16 hrs at 37°) and drug concentrations by radioimmunoassay. In addition, albumin and α1‐acid glycoprotein concentrations of the samples were measured by radial immunodiffusion. The mean ± SEM percentages of unbound DOX were: 20.4 ± 1.2 and 15.9 ± 1.2 in healthy subjects (n = 16) and patients (n= 15) respectively. and those of DDOX: 21.4 ± 0.9 and 19.0 ± 1.4 for healthy subjects and patients, respectively. There was a significant negative correlation between serum α1‐acid glycoprotein concentration and free fraction of DOX in both groups. In healthy subjects a significant negative correlation was also found between albumin concentrations and free fraction of both DOX and DDOX. Binding experiments with isolated protein fractions revealed that all of the total binding in plasma could be explained by binding to albumin and α1‐acid glycoprotein. The observed 2–4‐fold interindividual variability in the free fractions of these drugs is probably less important than the much larger variability in the total serum concentrations.
Effects of 3,4‐Dihydroxyphenylpyruvic Acid and its Triacetylated Derivative on DOPA Decarboxylase
Authors: Lindén I.‐B. , Neuvonen P. J. , Vapaatalo H.
Published: July 2010

Abstract:Various drugs have been studied in order to improve the bioavailability of L‐DOPA. In the present study, the α‐ketoacid of L‐DOPA, 3,4‐dihydroxyphenylpyruvic acid (DHPPA) and its fully acetylated derivative, triacetoxyphenylpyruvic acid (TAPPA), were investigated. These substances were shown to be equally strong DOPA decarboxylase inhibitorsin vitro.The inhibitory activity was, however, only about 1/2000 of that of carbidopa and 1/10 of that of L‐α‐methyldopa.In vivostudies in the rat showed that when either DHPPA or TAPPA was given orally concomitantly with L‐DOPA, only DHPPA, which is a transaminase inhibitor, enhanced the L‐DOPA induced rise in the cerebral dopamine concentration. TAPPA had, however, an enhancing effect on the L‐DOPA‐induced rise in the serum L‐DOPA concentration. The weak L‐DOPA‐sparing effect of TAPPA could be explained by its inhibitory effect on DOPA decarboxylase and the marked L‐DOPA‐sparing effect of DHPPA by its action on both transamination and decarboxylation.
Modification of Rat Brain 5‐Hydroxytryptamine Metabolism by Sublethal Doses of Organophosphate Agents
Authors: Prioux‐Guyonneau M. , Coudray‐Lucas C. , Coq H. M. , Cohen Y. , Wepierre J.
Published: July 2010

Abstract: The early and late effects of sublethal doses of two organophosphate agents (paraoxon and soman) on 5‐hydroxytryptamine (5‐HT) metabolism were investigated in several rat brain areas. Parallel determinations of acetylcholinesterase (AcChE) inhibition were performed. An increase in 5‐HT level was observed during the first phase of soman intoxication and a rise in 5‐hydroxyindol acetic acid (5‐HIAA) appeared in the early and late effects of both anticholinesterase agents with a predominant action in the striatum. These data suggested that paraoxon and soman induce a long‐lasting increase in 5‐HT turnover. This action cannot be related neither to the AcChE inhibition nor to the acetylcholine level.
Trimethoprim, Metioprim, Tetroxoprim, and RO 10‐5970 in Canine Bone
Authors: Iversen Peter , Madsen Paul O.
Published: July 2010

Abstract: The penetration of trimethoprim and three derivatives into bone tissue was investigated in a dog model. Our data demonstrated that the trimethoprim derivative RO 10–5970 concentrates well in bone tissue with median tissue‐to‐serum concentration ratios of 0.23 in cortical bone and 0.81 in both medulla and cancellous bone. The use of RO 10–5970 in osseous infections is appealing because oral administration is possible; therefore, clinical trials appear warranted.
Actions of Prenalterol, a New Cardioselective β1‐Agonist, Terbutaline and Isoprenaline on Electrophysiological and Mechanical Parameters of Guinea Pig Atrial and Papillary Muscles
Authors: Arlock Per
Published: July 2010

Abstract:The electrophysiological and mechanical effects of prenalterol on the isolated guinea pig atrial trabeculae and papillary muscles were compared with those of terbutaline and isoprenaline. Isoprenaline was the most potent of the drugs tested on all parameters studied. Prenalterol, on the other hand, failed to induce any changes in the atrial action potentials. The action potential duration was shortened in the atrial trabeculae by terbutaline and isoprenaline. All three substances shortened the action potential in the papillary muscles. In addition, isoprenaline increased the plateau height, and like terbutaline, increased the rate of repolarization during phase 3. Neither prenalterol nor terbutaline changed the effective refractory period in the atrial trabeculae whereas isoprenaline shortened it. All three substances shortened this parameter in the papillary muscles. The developed force and the rate of developed force were increased by all three substances. In addition. the total twitch duration was decreased.
Air Pollutant Sulfur Dioxide‐induced Alterations on the Levels of Lipids, Lipid Peroxidation and Lipase Activity in Various Regions of the Rat Brain
Authors: Haider S. Saleem , Hasan Mahdi , Khan N. H.
Published: July 2010

Abstract: The exposure of rats to SO2 (10 p.p.m.) for one hour daily for 30 days caused depletion of total lipids in all brain areas. The contents of phospholipid were elevated in cerebellum and brain stem, but were depleted in cerebral hemisphere. Cholesterol levels showed an increase in various brain regions. On the other hand, gangliosides were increased in cerebellum and brain stem, but were decreased in cerebral hemisphere. Interestingly, cholesterol/phospholipid ratio was increased in different regions of the brain. Lipase activity was elevated in cerebral hemisphere. Lipid peroxidation showed marked increment in whole brain and in all the brain areas studied. The results suggest that SO2‐exposure induces degradation of lipids. Interestingly, the lipid contents are affected differentially in the various parts of the brain.
Citalopram‐induced Generalized Lipidosis in Rats
Authors: Lüllmann‐Rauch Renate , Nässberger Lennart
Published: July 2010

Abstract: This study was focussed on the question of whether or not the potential antidepressant citalopram, which is an amphiphilic cationic compound, can induce generalized lipidosis in animals. In a short term experiment, female rats were treated with a single oral dose (100 mg/kg) and the lymph node was examined by electron microscopy; a significant number of lymphocytes showed lamellated inclusions indicating lipidosis. In a subchronic experiment (7 weeks) female rats received 140 mg/kg per day, and several organs were examined. Marked lipidosis‐like alterations were found in lymph node, adrenal cortex and medulla, kidney, lung and in a sympathetic ganglion. Mild lysosomal alterations were found in hepatocytes and retinal pigment epithelium. Lipidosis was very weak, or absent, in retinal ganglion cells, trigeminal ganglion cells and in hypothalamic neurosecretory perikarya. In addition, citalopram produced myopathic alterations in soleus muscle resembling those previously induced with other cationic amphiphilic drugs. Myopathy persisted during a drug‐free recovery period of 4 weeks, whereas generalized lipidosis was reversible within 2–4 weeks. The present results support a previously proposed concept concerning the structure‐response relationships underlying drug‐induced lipidosis.
The Metabolism of Prostaglandin E2 is Decreased by High‐ and Medium‐Tar but Not by Low‐Tar Cigarette Smoke in Isolated Rat Lungs
Authors: Matintalo Martti , Kuusisto Timo , Männistö Jussi , Uotila Pekka
Published: July 2010

Abstract: The effects of smoke from low‐, medium‐ and high‐tar cigarette brands on the metabolism of prostaglandin E2(PGE2) were investigated in isolated rat lungs. When isolated lungs were ventilated with smoke of high‐ or medium‐tar cigarettes during an infusion of PGE2 into the pulmonary circulation, the amount of unmetabolized PGE2 was increased and that of 15‐ketometabolites (15‐keto‐PGE2 and 13, 14‐dihydro‐l5‐keto‐PGE.2 together) was decreased in the perfusion effluent compared to air ventilated control lungs. This decrease in the pulmonary metabolism of PGE2 was seen by both filter and non‐filter high/medium‐tar cigarettes. When isolated rat lungs were ventilated with smoke of low‐tar cigarettes no change in the metabolism of PGE2 was detected. The pressor response of the vascular bed to the infusion of PGE2 was inhibited with smoke of both low‐ and high‐tar cigarettes.
Hepatic Elimination of Femoxetine in Pig during Intravenous Infusion
Authors: Keiding S. , Mengel H. , Lund J.
Published: July 2010

Abstract: Hepatic elimination of femoxetine was studied in six anaesthetized pigs during intravenous administration. Femoxetine was given into ajugular vein as a constant infusion of 0.4–7.2 mg/min. in five pigs and as a bolus injection of 383 mg in one pig. The hepatic extraction was high (92–98 %) corresponding to earlier findings of 91–99% when femoxetine was infused into the portal vein in pig or given orally to man. The urinary excretion was low, less than 5% of the dose, and the estimated extrahepatic metabolism was not significantly different from zero.
Effect of Naloxone on the Hypotensive Action of Clonidine in the Conscious, Normotensive Goat
Authors: Eriksson Lea , Tuomisto Leena
Published: July 2010

Abstract:The possible involvement of opioid receptors in the effects of clonidine was studied in conscious, normotensive goats. Clonidine was infused intravenously followed by an intravenous injection of naloxone. Blood pressure was recorded through an intraarterial catheter. All doses of clonidine (0.2–7 μg/kg) significantly lowered blood pressure and decreased heart rate. Hypotension after 0.2–0.7 μg/kg of clonidine was significantly reduced by naloxone (1 mg/kg), while naloxone did not antagonize hypotension induced by the larger doses of clonidine. The bradycardiac effect of 0.7–2 μg/kg of clonidine was reduced by naloxone while that of 0.2 and 7 μg/kg was not. Clonidine also induced sedation and respiratory irregularity, but these changes were not modified by naloxone. Opioid mechanisms possibly participate in the hypotensive action of clonidine, but less in the normotensive animal than in spontaneously hypertensive animals.
An Enflurane‐Nitrous Oxide Semi‐Open Anaesthesia Method for Small Experimental Animals
Authors: Karhunen Pekka J. , Sippel Helmuth , Ertama Pertti
Published: July 2010

Abstract:An inhalation anaesthesia method for small laboratory animals applicable in pharmacological and toxicological experiments is presented. The arrangement allows easy and continuous control of anaesthesia level even in intoxicated animals during experimental operations. Hypoxia is avoided by continuous oxygen supply. The simultaneous use of enflurane and nitrogen is safe and minimizes the disturbances of anaesthesia on the biotransformation of experimental substances. The anaesthesia is smooth producing sufficient muscle relaxation for e.g. abdominal operations without depressing the cardiovascular function.
Influence of Anoxia and Dinitrophenol on the Phosphorylase a Activity and the Cyclic Nucleotide Content of Smooth Muscle
Authors: Arnqvist H. , Groth H. , Lundholm L. , Pettersson G. , Wingren G.
Published: July 2010

Abstract: The effect of anoxia or 2,4‐dinitrophenol (DNP) on the phosphorylase activity and the cyclic AMP and the cyclic GMP content was studied in smooth muscle preparations. When the aerobic conditions were changed to anaerobic in experiments on bovine mesenteric artery, there was a significant increase in the activity of phosphorylase a during the first 60 min. We had observed a reduction of the glycogen content of the artery during this time period, which accounted for about 2/3 of the increase in lactate production (Pasteur effect). Under anaerobic conditions the content of cyclic AMP in the vessel was not changed, and the increase in phosphorylase a activity was not inhibited by a blockade of adrenergic β‐receptors. DNP, which like anoxia inhibits the mitochondrial production of ATP, increased the phosphorylase a activity to the same extent as anoxia. Anoxia and DNP also enhanced the activity of phosphorylase a in pig thoracic aorta and rabbit colon smooth muscle. In thoracic aorta both anoxia and DNP produced a more transient and smaller increase in the phosphorylase a activity than in the mesenteric artery. The Pasteur effect was also relatively smaller (100%) in thoracic aorta than in mesenteric artery (400%). It is suggested that an anoxic increase in the phosphorylase a activity participates in the Pasteur effect in smooth muscle.
The Effect of Some Drugs with Purported Antianoxic Effect on Veratridine‐induced Purine Release from Isolated Rat Hypothalamic Synaptosomes
Authors: Fredholm Bertil B. , Lindgren Eva , Lindström Karin , Vernet Louise
Published: July 2010

Abstract: Several drugs claimed to protect against anoxic damage to the brain and/or to aleviate symptoms of senility were tested for their ability to influence purine overflow from hypothalamic synaptosomes. Theophylline did not influence the total purine release but tended to decrease the nucleoside and increase the nucleotide release. Cyclic nucleotide phosphodiesterase inhibitors were ineffective, whereas drugs that inhibit carrier mediated nucleoside transport inhibited veratridine‐induced purine release. Some ergot derivatives, some vinca‐analogues and the vasodilator ifenprodil also decreased stimulated purine release, but their effect could not be attributed to adenosine transport inhibition. The results suggest that drugs that are reported to aleviate symptoms of anoxic damage or senility may inhibit the release of adenosine and related compounds in the central nervous system. Some possible reasons why a decreased purine release may protect against ischaemic brain damage are discussed.
Role of Selenium in Protection against Lead Intoxication
Authors: Flora S.J.S. , Singh Surendra , Tandon S.K.
Published: July 2010

Abstract:The administration of selenium concomitantly with lead in rats restrained the lead induced enzymuria, proteinuria, enhanced urinary excretion of δ‐aminolevulinic acid, inhibition of the activities of certain renal enzymes, blood δ‐aminolevulinic acid dehydratase and blood, liver and kidney uptake of lead. The protective effect of selenium against lead toxicity may be attributed to a competition between selenium and lead for binding with the functional bioligands or to thein vivoformation of lead selenide.
Effect of Chronic Ethanol Ingestion on Liver and Plasma Protein Synthesis in Galactosamine‐induced Hepatitis in Rats
Authors: Nadkarni G. D. , Pestonjamasp K. N. , Deshpande U. R.
Published: July 2010

Abstract: In rats a single injection (330 mg/kg) of D‐galactosamine significantly inhibited in vivo incorporation of 14C‐amino acids into fibrinogen, seromucoids and total liver proteins, but not albumin, by one third. Prior chronic exposure to ethanol (5 g/kg/day for 6 weeks) potentiated the inhibition of synthesis of all protein fractions (including albumin) up to about 50%. Propylthiouracil had no beneficial but deleterious effect against this potentiation of hepatotoxicity.
Effects of Phenoxyherbicides and Glyphosate on the Hepatic and Intestinal Biotransformation Activities in the Rat
Authors: Hietanen Eino , Linnainmaa Kaija , Vainio Harri
Published: July 2010

Abstract: The effects of phenoxyacid herbicides 2,4‐D (2,4‐dichlorophenoxyacetic acid) and MCPA (4‐chloro‐2‐methylphenoxyacetic acid), clofibrate, and glyphosate on hepatic and intestinal drug metabolizing enzyme activities were studied in rats intragastrically exposed for 2 weeks. The hepatic ethoxycoumarin O‐deethylase activity increased about 2‐fold with MCPA. Both 2,4‐D and MCPA increased the hepatic epoxide hydrolase activity and decreased the hepatic glutathione S‐transferase activity. MCPA also increased the intestinal activities of ethoxycoumarin O‐deethylase and epoxide hydrolase. Glyphosate decreased the hepatic level of cytochrome P‐450 and monooxygenase activities and the intestinal activity of aryl hydrocarbon hydroxylase. Clofibrate decreased the hepatic activities of UDPglucuronosyltransferase with p‐nitrophenol or methylumbelliferone as the substrate. Also 2,4‐D decreased the hepatic activity of UDPglucuronosyltransferase with p‐nitrophenol as the substrate. MCPA decreased the intestinal activities of UDPglucuronosyltransferase with either p‐nitrophenol or methylumbelliferone as the substrate. The results indicate that phenoxyacetic acids, especially MCPA, may have potent effects on the metabolism of xenobiotics. Glyphosate, not chemically related to phenoxyacids, seems to inhibit monooxygenases. Whether these changes are related to the toxicity of these xenobiotics remains to be clarified in further experiments.
N,N‐Dimethylformamide‐induced Effects on Hepatic and Renal Xenobiotic Enzymes with Emphasis on Aldehyde Metabolism in the Rat
Authors: Elovaara E. , Marselos M. , Vainio H.
Published: July 2010

Abstract:Male Wistar rats were dosed with N,N‐dimethylformamide (DMF) in drinking water at four concentration levels (0, 0.1, 0.5 or 1.0 g/l) for 2 or 7 weeks. Upon evaluation of the effects in the liver increased values were found for the following parameters: liver/body weight‐ratio, GSH content, ethoxycoumarin O‐deethylase and UDPglucuronosyltransferase activities. The GSH content, deethylase activity and, transiently, the glucuronidation activity were slightly increased also in the kidneys. Oxidative N‐demethylation of DMF by hepatic microsomesin vitrowas not enhanced by oral treatment. No DMF‐dependent formaldehyde liberationin vitrocould be detected under conditions where formaldehyde liberation from N,N‐dimethylnitrosamine could be demonstrated. However, the endogenous rate of formaldehyde generation by liver microsomes isolated from DMF‐treated rats was enhanced with the highest oral dose of DMF. The daily intake of DMF lowered the activities of both formaldehyde and propionaldehyde dehydrogenases in the liver soluble fraction. No inhibition of these dehydrogenases was shownin vitroby DMF (≤10 mM) or by its main urinary metabolite N‐methylformamide (≤10 mM). The observed impairment of aldehyde oxidation in liver and kidneys of the rat after the DMF intake could explain the mechanism behind the alcohol intolerance observed in man after DMF‐exposure.
The LD50test
Authors: Paget E.
Published: July 2010

AbstractThe nature of the LD50test and its central place in the conceptual development or pharmacology is reviewed. The results of the test and possible uses are outlined. Some guidelines are set out for the development of alternatives to LD50tests. Some circumstances are suggested in which it seems likely that some form of the test will continue to be required. It is concluded that the problem of replacing the LD50test with apparently more elegant methods is part of the larger and more fundamental problem of bringing science to the study and regulation of toxicology.
Computer methods for the assessment of toxicity.
Authors: Wold S. , Hellberg S. , Dunn W. J.
Published: July 2010

Abstract The prediction of the biological activity of chemical compounds by means of mathematical models is discussed. Biological activity of chemicals, including their toxicity on man and other biological organisms and systems, involves too complex phenomena to presently be predictable by fundamental models such as ab initio quantum mechanical models or statistical mechanical models.

Hence one takes recourse to semi‐empirical and empirical models which relate the variation in chemical structure of chemical compounds to the variation in their measured biological activity, e.g. toxicity in one or several test systems. These models are “calibrated” on series of similar compounds with “known” toxicity, the training set. Thereafter the models can — in fortunate cases — be used to predict the toxicity of compounds which are structurally similar to the training set compounds.

The formulation and applicability of semi‐empirical and empirical models relating chemical structure to biological activity is discussed. Causes and remedies for commonly encountered fallacies are presented.
The Effect of Alkylxanthines and Other Phosphodiesterase Inhibitors on Adenosine‐Receptor Mediated Decrease in Lipolysis and Cyclic AMP Accumulation in Rat Fat Cells
Authors: Fredholm Bertil B. , Lindgren Eva
Published: July 2010

Abstract:Cyclic AMP accumulation and glycerol release were studied in isolated rat fat cells. Both processes were inhibited by R‐site specific adenosine analogues (L‐PIA>NECA>2‐chloro‐adenosine>D‐PIA), but poorly or not at all by the P‐site selective analogue SQ 22,536. The effect of a series of xanthine derivatives and of some structurally unrelated phosphodiesterase inhibitors as inhibitors of 2‐chloro‐adenosine induced inhibition of NA stimulated cyclic AMP accumulation and lipolysis was subsequently examined. The 2‐chloro‐adenosine effect on cyclic AMP accumulation was antagonized by the xanthines with the following order of potency: DPX>8‐phenyl‐theophylline>8‐p‐sulpho‐phenyl‐theophylline>verrophylline>IBMX>theo‐phylline>HWA 285>pentoxiphylline>caffeine>7‐benzyl IBMX>theobromine>enprofylline>ZK 62,711. The rank order potency of xanthines against the antilipolytic effect of 2‐chloro‐adenosine was the same with two notable exceptions: the two potent phosphodiesterase inhibitors 7‐benzyl‐IBMX and ZK 62,711 were more than 20 times more potent as inhibitors of the antilipolytic effect of 2‐chloro‐adenosine. The results show that antagonism of adenosine analogue‐induced antilipolytic effects is a convenient assay for adenosine antagonistic potency of drugs, except for drugs with a high potency as phosphodiesterase inhibitors. The lipolytic potency of the xanthine derivatives was also studied. The ability of the xanthines to stimulate basal and noradrenaline stimulated lipolysis was generally in agreement with their potency as adenosine antagonists. Adenosine deaminase induced lipolysis was stimulated by potent phosphodiesterase inhibitors.
Cardiovascular Effects of Copper in Pithed Rats
Authors: MacDonald Ewen
Published: July 2010

Abstract: The pithed rat preparation was used to study the effects of copper (as cupric chloride) on the release and re‐uptake of noradrenaline from sympathetic nerves. At the highest concentration which could be tested without failure of the preparation, there was a slight prolongation in the duration of the tachycardia obtained by electrical stimulation of the cardioacceleratory nerves to the heart. However, the tachycardia obtained after intravenous injection of tyramine was also similarly prolonged from which it is concluded that the phenomenon is not related to inhibition of neuronal re‐uptake but is more likely due to alterations in the metabolism of noradrenaline or in the factors governing its diffusion from the synapse. Copper itself caused a dose‐dependent increase in blood pressure which was not due to release of noradrenaline from sympathetic neurones. In addition to its own vasoconstrictor effect, it inhibited the increase in blood pressure obtained after administration of phenylephrine, tyramine and vasopressin. Since the extent of the inhibition of all three compounds was similar, it is concluded that the effect is non‐specific inhibition of blood vessel contractility. In the pithed rat preparation, as in the chick biventer preparation (Lin‐Shiau & Fu 1980), the acute effects of copper seem to be more clearly seen on muscle with little evidence being available to support potent neurotoxicity.
Quantitative Liver Functions after Administration of Allyl Alcohol to Rats
Authors: Poulsen H. E. , Korsholm B.
Published: July 2010

Abstract: In rats a single dose of allyl alcohol (100 μl per kg body weight) was given to produce periportal liver damage. Prothrombin index was reduced to a minimum after 12 hours and reestablished after 24 hours. The galactose elimination capacity was not changed. Hepatic glutathione content was unchanged for the first 24 hours but was then elevated twofold. Microsomal p‐nitro‐anisole demethylation showed a slight initial increase and a subsequent reduction. The pattern of these changes is similar to that seen after centrilobular liver damage from acetaminophen overdose (Poulsen et al. 1981a; Poulsen et al., unpublished results), with the exception that the latter causes glutathione depletion. This indicates that in chemical liver damage ribosomal function, e.g. protein synthesis and drug hydroxylation, is more vulnerable than cytosolic phosphorylation of carbohydrate.
Serum Albumin ‐ A Non‐Saturable Carrier
Authors: Brodersen Rolf , Honoré Bent , Larsen Frederik Grønhøj
Published: July 2010

Abstract: The shape of binding isotherms for sixteen ligands to human serum albumin showed no signs of approaching saturation at high ligand concentrations. It is suggested that ligand binding to serum albumin is essentially different from saturable binding of substrates to enzymes, of oxygen to haemoglobin, etc. Binding to serum albumin appears to be non‐saturable.
Alkylation of Guanosine by Phosphoramide Mustard, Chloromethine Hydrochloride and Chlorambucil
Authors: Kallama Seija , Hemminki Kari
Published: July 2010

Abstract: Guanosine was reacted in vitro with phosphoramide mustard, chloromethine hydrochloride, and chlorambucil. The products were isolated by HPLC and characterized by UV and fluorescence spectroscopy, and C‐8 tritium exchange. The primary products were 7‐alkylguanosines according to such evidence. Phosphoramide mustard had 1/10 of the apparent alkylation activity of two other mustards. The primary 7‐alkylguanosines were unstable at pH 7.4 and 37°; t1/2 were 3 min. for chloromethine hydrochloride, 2.7 hrs for chlorambucil and 3.0 hrs for phosphoramide mustard. Both dechlorination at the unbound arm of the mustard and imidazole ring opening og guanosine appeared to account for such instability.
Pharmacokinetics and Metabolism of Sulphadiazine in Neonatal and Young Pigs
Authors: Friis Christian , Gyrd‐Hansen Nils , Nielsen Poul , Olsen Carl‐Erik , Rasmussen Folke
Published: July 2010

Abstract:The pharmacokinetics of sulphadiazine was studied in newborn, 1 week, and 8 weeks old piglets after intravenous administration of 60 mg/kg. Kinetic parameters were calculated using a two compartment open model. Steady state volume of distribution averaged 0.62, 0.56, and 0.48 1/kg at birth, 1 week, and 8 weeks, respectively. Elimination half‐life decreased from 455 rain, at birth to 322 min. at 1 week and 157 min. at 8 weeks leading to a rise in body clearance from 0.99 to 2.20 ml/min./kg during the same age period. Urinary excretion data indicated that the increase in body clearance reflects maturational changes in both renal function and metabolic capacity. Although renal clearance increased several times more than metabolic clearance, metabolism remained the main contributor to elimination of SDZ at all ages. Metabolism of SDZ involves two important pathways ‐ acetylation and aromatic hydroxylation; the former being well developed at birth, while the latter increased markedly during the age period studied.
The Influence of Intravenous Furosemide on the Renal Excretion Pattern of Protein and Protein Degradation Products
Authors: Andreasen F. , Hansen U. , Husted S. E. , Mogensen C. E.
Published: July 2010

Abstract: To assist the attending physician who may have difficulties in deciding whether observed deviations from normal renal physiology are disease‐induced or diuresis‐induced we studied urinary excretion rate of proteins and protein degradation products in eight healthy male volunteers between 60 and 70 years. After a 24 hr control period in the ward the subjects received 80 mg furosemide intravenously. The 24 hr creatinine clearance was reduced from 95 ± 9 to 83 ± 6 ml/min. (P > 0.05). The reduction in the 24 hr carbamide clearance from 35.8 ± 9.4 to 33.1 ± 6.2 ml/min. was not significant. The urinary pH was significantly increased during the first hour but after that the pH showed a fall which was significant during 2–8 hours after the injection. Initially the urate excretion showed an apparent increase but from 1–8 hours after the injection significantly less urate was excreted. The 24 hr urate clearance was reduced by furosemide from 5.3 ± 1,6 to 3.4±1.1 ml/min. (P>0.05) and the amount of urate excreted was reduced from 2.6 to 1.6 mmol per 24 hrs (p = 0.05). The excretion rate of (32‐microglobulin was reduced (P > 0.01) whereas the excretion rate of albumin was increased (P>0.05).
Comparison of the Effect of DDE on the Ca Metabolism of the Eggshell Gland and its Subcellular Fractions of the Duck and the Domestic Fowl
Authors: Lundholm C. E.
Published: July 2010

Abstract: In a strain of ducks sensitive to the eggshell‐thinning effect of p‐p'‐DDE, administration of 40 mg/kg of the compound in the food for 45 days reduced the eggshell index (EI) by 13% and the content of calcium in the fluid of the shell gland forming an eggshell by 36%, and raised the calcium content of the shell gland mucosa by 19%, compared with the control values. DDE inhibited the translocation (secretion) of calcium between the gland mucosa and the uterine cavity. The ATP‐dependent binding of Ca2+ to the subcellular fractions of the gland mucosa was reduced in DDE‐treated ducks. The Ca2+ binding to a microsomal subfraction (FI) rich in fragments of the plasma membrane was reduced by 16%, whereas that to a subfraction Fill which bound Ca2+ at a very high rate was reduced by 36%. The latter may contain calcium‐secreting granules of the gland. In the mitochondrial fraction the Ca2+ binding was reduced by 35%. In the domestic fowl DDE did not lower EI or interfered with the translocation of calcium between the shell gland mucosa and uterine cavity. DDE administration increased the Ca2+ binding to FI by 26%; the binding to other subfractions was not changed significantly. DDE may interfere with the stimulus‐secretion mechanism of the eggshell gland in ducks through its effect on Ca2+ binding.
Slow Binding of Progesterone to Plasma Proteins
Authors: Einer‐Jensen Niels
Published: July 2010

Abstract: The uptake of 3H‐ and 14C‐progesterone (P) from bovine plasma into the wall of a 1 m PVC‐catheter was measured. Fifty ml of bovine plasma (22°) was pumped through the catheter (mean transit time 2 or 10 sec. per m). The 14C‐P was added one hour previously while the 3H‐P was continuously added at the inlet. The uptake of the isotopes into ten cm sections of the catheter was measured by liquid scintillation counting. The uptake of 3H‐P was always higher than that of 14C‐P indicating that the binding to plasma proteins does not reach equilibrium within 10 sec. Preincubation with 100 ng/ml cold P further increased the difference in uptake. The increased fraction of accesible steroid hormone may be of physiological importance, because a high fraction of hormone exchanged from the ovarian vein to the ovarian artery may reach the ovary and the tube in a physiologically active form.
On the Use of Enzyme Inhibitors to Study the Synthesis and Utilization of Brain GABA
Authors: Lindgren Silvana , Andén Nils‐Erik
Published: July 2010

Abstract: Changes in the GABA concentration in different parts of the rat brain were studied following inhibition of the glutamic acid decarboxylase or the GABA‐α‐ketoglutaric acid aminotransferase. The GABA concentration was reduced by the decarboxylase inhibitors 4‐deoxypyridoxine and isoniazid, but not by 3‐mercaptopropionic acid and DL‐allylglycine. The aminotransferase inhibitor γ‐acetylenic GABA increased the concentration of GABA and this effect was markedly inhibited by 3‐mercaptopropionic acid and partly by 4‐deoxypyridoxine and isoniazid. The 4‐deoxypyridoxine‐induced decrease in the GABA concentration was approximately maximal after 400 mg/kg intraperitoneally and 90 min. The brain DOPA decarboxylase activity in vivo was not inhibited by 4‐deoxypyridoxine. The GABA concentration in the substantia nigra was reduced by 75 per cent 4 days after section of the striato‐nigral GABA neurones. In the denervated substantia nigra, 4‐deoxypyridoxine did not change the concentration of GABA whereas the effect of γ‐acetylenic GABA was reduced by 70 per cent.
Determination of Conjugated Dopamine in Cerebrospinal Fluid from Humans and Non‐human Primates with High Performance Liquid Chromatography using Electrochemical Detection
Authors: Scheinin Mika , Seppala Time , Koulu Markku , Linnoila Markku
Published: July 2010

Abstract: A simple and reliable procedure for the determination of conjugated dopamine (DA) in cerebrospinal fluid (CSF) is described. The conjugate, presumably a sulfate, is conveniently hydrolyzed in 0.4 M sulfuric acid at 95°. Thereafter, dopamine is quantitated using HPLC with electrochemical detection. Sensitivity (0.5 pmol/ml) is sufficient for clinical studies. Only 400 ul of CSF are required for the assay. The within assay coefficient of variation was 3.2% for conjugated DA (concentration of 11.8 pmol/ml). In a material consisting of 261 samples of lumbar CSF from unmedicated psychiatric patients and normal control subjects, a concentration range of 1.3–21.7 pmol/ml was found. No clear differences were evident between the major diagnostic groups.
A Comparative Study of Guanine N7‐Alkylation in Mice in Vivo by the Organophosphorus Insecticides Trichlorphon, Dimethoate, Phosmet and Bromophos
Authors: Dedek Wolfgang , Grahl Rolf , Schmidt Reiner
Published: July 2010

Abstract: Following intraperitoneal administration to male mice (strain AB Jena/Halle) of 14C‐methyllabelled trichlorphon, dimethoate, phosmet and bromophos, 10–20 Ci/mol, in dosages of 0.06–0.55 mmol/kg, DNA from liver and kidneys was analyzed for 14C in N‐7 methylguanine (7‐MeG). The extents of methylation were in the range of 5–10 μmol 7‐MeG/mol guanine for trichlorphon and dimethoate and of 0.2–0.4 for phosmet and bromophos, for high doses, respectively Excretion half‐lives of 7‐MeG were differing between trichlorphon (5 hrs, high dose, and 15–17 hrs, low dose) and dimethoate (23–160 hrs, high dose). The extents of methylation at 0–6 of guanine were estimated to be around 0.01 μmol 0–6 MeG/mol guanine for high doses of organophosphates of sufficient water solubility. Factors associated with the partition of organophosphates in mammalian systems are useful for estimating DNA attack by organophosphates in mammals in vivo.
Allergic and Pseudo‐allergic Reactions Caused by Penicillins, Cocoa and Peppermint Additives in Penicillin Factory Workers Examined by Basophil Histamine Release
Authors: Meller N. E. , Skov P. Stahl , Norn Svend
Published: July 2010

Abstract: Allergic and pseudo‐allergic reactions were examined in penicillin factory workers exposed to the dust of preparations of pivampicillin and pivmecillinam. Among 14 workers basophils from five persons showed histamine release by challenge with penicillins, whereas no release was observed in controls of non‐atopic individuals not working with the manufacturing of penicillin. Positive skin response was obtained in four workers by path testing and in three persons by scratch test revealing late but no immediate response. All the eight workers who were also exposed to flavour additives used in the penicillin preparations showed histamine release by cocoa and peppermint. The release was not changed by removal of immunoglobulins from the basophil cell surface and the additives caused a similar release in the controls. The histamine release caused by cocoa and peppermint therefore depend on non‐immunological mechanisms, i.e. pseudo‐allergic reactions which might contribute to the symptoms in penicillin factory workers.
Effects of Physostigmine, Paraoxon and Soman on Brain GABA Level and Metabolism
Authors: Coudray‐Lucas C. , Prioux‐Guyonneau M. , Sentenac H. , Cohen Y. , Wepierre J.
Published: July 2010

Abstract: The effects of sublethal doses of physostigmine, paraoxon and soman on GABA levels and metabolism were studied in small rat brain areas (hypothalamus, striatum, cerebellum, rest of the brain). Physostigmine induced a significant decrease in striatal GABA level and a reduction of synthesis index in the rest of the brain while organophosphates have little or no effect on GABA level and metabolism. This work provides new data about the physostigmine effect on brain GABA which could be related to the action of the anticholinesterase agents on other non‐cholinergic neurotransmitters.
Biochemical Effects and Decreased Body Burden of Cyclopentanone by Extended Vapour Inhalation
Authors: Elovaara Eivor , Pfäffli Pirkko , Savolainen H.
Published: July 2010

Abstract: Male Wistar rats exposed intermittently to cyclopentanone vapour at 50, 100 or 300 p.p.m. 6 hrs daily 5 days a week for 1 to 15 weeks showed brain and perirenal fat solvent concentrations which correlated to the exposure although they decreased at the later stages of the experiment. Cyclopentanone caused almost no effects on liver drug metabolizing enzymes or aldehyde dehydrogenase activities while an early increase in the kidney 7‐ethoxycoumarin O‐deethylase was found after 1 week without a concomitant increase in the cytochrome P‐450 content. This effect was abolished later so that an enhancement was found only at the highest exposure level after 15 weeks. Postmitochondrial fractions isolated from liver of exposed animals metabolized cyclopentanone more actively than controls after 15 weeks.
Comparison of Electrophysiological and Mechanical Effects of Droxicainide and Lidocaine on Heart Muscle Isolated from Rats
Authors: Helgesen Knut G. , Kristiansen Olav , Refsum Helge
Published: July 2010

Abstract: A new antiarrhythmic drug, droxicainide, was compared with lidocaine in order to evaluate droxicainide's effect on heart muscle. Dose‐response curves for electrophysiological and mechanical effects of the two drugs on spontaneously beating atria, electrically stimulated atria and papillary muscles isolated from rats were obtained. After increasing doses of both droxicainide and lidocaine sinus node automaticity decreased, atrial and ventricular excitability and contractile force decreased and refractoriness increased. The effects of the two drugs on atrial and ventricular muscle were qualitatively and quantitatively the same, but droxicainide was less potent. The results fit well with the concept that droxicainide is a class 1 antiarrhythmic drug.
Neurotoxic Effects of Disulfiram on Autonomic Nervous System in Rat
Authors: Savolainen Kai , Hervonen Heikki , Lehto Veli‐Pekka , Mattila Mauri J.
Published: July 2010

Abstract:Two groups of male Wistar rats weighing about 140 (WI) and 200 g (WII) and a group of Sprague‐Dawley (S.D.) rats (140 g) received oral disulfiram 220–580 mg/kg (DSF) daily for one or three weeks. Isolated ilea of both control and treated rats showed similar responses to acetylcholine, but the responses to 5‐hydroxytryptamine (5‐HT) were decreased after one and three weeks’treatment in the WI and SD rats. Pretreatment with reserpine intensified this effect in treated WI rats. A distinct decrease in the histochemical reactivity for the acetylcholinesterase and the non‐specific cholinesterase was observed in the nerve plexuses of the gut wall indicating a DSF‐induced nerve damage. Autonomic (cholinergic) nerves seemed thus to be affected by DSF. The two rats strains studied did not differ in their responses to 5‐HT.