bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurochemical and Behavioural Effects of Long‐term Intermittent Inhalation of Xylene Vapour and Simultaneous Ethanol Intake
Authors: Savolainen H. , Pfäffli P. , Helojoki M. , Tengén M.
Published: July 2010

Abstract Two‐month‐old male Wistar rats were exposed to 300 p.p.m. of xylene vapour with simultaneous ethanol ingestion for 5 to 18 weeks. Neurochemical effects of mere vapour inhalation included an increase in microsomal superoxide dismutase activity in brain at the end of the experiment. Concomitant ethanol ingestion added significantly to the xylene‐induced effects by causing increased proteolysis at the 9th and 14th week of exposure whereas cerebral superoxide dismutase failed to increase in these animals.

Preening frequency decreased transiently in ethanol and in xylene groups at 6 and 9 to 12 weeks, respectively, whereas increased ambulation occurred only in the xylene ‐ ethanol group after 12 and 14 weeks of exposure. The behavioural effects were therefore different in the combined exposure, and our biochemical and behavioural observations may point at significant interaction of both solvents although the biochemical mechanisms remain largely unexplained.
Effect of Sodium Fluoride on Protein and DNA Synthesis, Ornithine Decarboxylase Activity, and Polyamine Content in LS Cells
Authors: Hongslo Jan K. , Holland Roy I.
Published: July 2010

AbstractSodium fluoride exhibited a dose dependent inhibitory effect on protein and DNA synthesis at concentrations from 1.3 mM in growing LS cells. The activity of ornithine decarboxylase (ODC) was slightly stimulated by 0.5 mM‐NaF, but inhibited at 1.3 mM and above. The reduced enzyme activity seemed to be due to a reducedde novoformation of the enzyme caused by an inhibition of the protein synthesis. In spite of a reduction in ODC‐activity, fluoride had no effect on the cellular polyamine content during the experimental period (10 hours).
The Effect of Fluoride on the Cellular Uptake and Pool of Amino Acids
Authors: Holland Roy I. , Hongslo Jan K.
Published: July 2010

AbstractFluoride decreased the initial uptake of 2‐aminoisobutyric acid (AIB) in LS cells only in high (supralethal) concentrations and after several hours of exposure. The steady state level of AIB seemed somewhat more sensitive as it was halved after 23 hours exposure to 6 mM‐NaF. The cellular levels of some natural amino acids were also reduced by fluoride. However, cells resistant to fluoride showed equally lowered levels of amino acids, indicating that the observed effect of fluoride on cellular amino acid levels may be of little importance.
Inter and Intra Laboratory Variation of Digoxin Radioimmunoassay in Sweden
Authors: Bergdahl Björn , Dahlströrn Gunilla , Molin Lilian , Bertler Åke
Published: July 2010

Abstract Samples from two pools were sent 10 times to 27 laboratories for assay of digoxin. One pool contained digoxin 2.60 nmol/1 in normal plasma (SP); the other was pooled plasma from patients treated with digoxin (PP). Ten radioimmunoassay (RIA) methods were used. The mean of SP assays was 2.59 nmol/1, not significantly different from 2.60 nmol/1. The mean of PP determinations was 2.46 nmol/1. Within each of the 10 assay rounds, the concentrations showed an almost twofold variation and S.D. averaged 0.33 nmol/1 and 0.31 nmol/1 for SP and PP respectively. Significant differences (P<0.001) were found between mean concentrations obtained for the pools at various laboratories (SP range 2.15‐2.85 nmol/1; PP range 2.12‐2.72 nmol/1). The laboratory means obtained for SP and PP correlated significantly (P<0.001). Nevertheless, significant (P<0.01) variations between laboratories were found also concerning the mean difference between SP and PP concentrations. The interassay SD of the assays differed significantly between laboratories (range 0.05‐0.61 nmol/1). Between and within groups of laboratories using the same RIA method and between various types of laboratories, differences were also found concerning both accuracy and precision of the assays. It is concluded that a better control of digoxin assay is needed.
The Binding of Furosemide to Serum Proteins in Elderly Patients: Displacing Effect of Phenprocoumon
Authors: Andreasen F. , Husted S.
Published: July 2010

Abstract:The percentual binding of furosemide (5 μg/ml) was slightly but significantly lower in serum from elderly patients than in serum from normal blood donors (96.5±0.7 versus 97.7±0.3). A significant positive correlation was demonstrated between protein binding and albumin concentration in serum. The reduced binding in the elderly could be explained by an observed decrease in the concentration of albumin in the elderly. The percentual binding did not change in samples obtained during the first hour after the intravenous administration of 40 mg furosemide. Of 4‐chloro‐5‐sulfamoyl antranilic acid (CSA) and antranilic acid (A) about 60% were bound to serum proteinsin vitroand none of these two compounds affected the protein binding of furosemide. The addition of phenprocoumon (PPC) caused significant decreases in the percentual binding of furosemide in serum (5 μg/ml) at PPC values of 10 μg/ml and more. The effect of PPC on the binding of furosemide was studiedin vivoin 7 patients receiving 40 mg furosemide intravenously without and with the simultaneous intravenous administration of PPC (3 mg per 10 kg body weight). In good accordance with thein vitroexperiments the modest average decrease in furosemide binding, caused by concentrations of PPC not exceeding 6.2 μg/ml, was not significant.
The Effect of Maternally Inhaled Styrene on Embryonal and Foetal Development in Mice and Chinese Hamsters
Authors: Kankaanpää Jari T. J. , Elovaara Eivor , Hemminki Kari , Vainio Harri
Published: July 2010

Abstract: Pregnant mice and Chinese hamsters were exposed to styrene 6 hrs daily during the period of major organogenesis via inhalation in concentrations 250 p.p.m., and 300, 500, 750 and 1000 p.p.m., respectively. Both in mice and in Chinese hamsters embryotoxicity was raised. Some minor skeletal malformations (rib fusions, extra ribs) were noted in mice but not in Chinese hamsters.
Zimelidine‐Induced Lipidosis in Rats
Authors: Bockhardt Hans , Lüllmann‐Rauch Renate
Published: July 2010

Abstract: This study was aimed at the question of whether or not the antidepressant zimelidine, which is an amphiphilic cationic compound, can induce generalized lipidosis in animals. Rats were chronically treated with high oral doses (80 mg/kg) of the drug, and several organs were examined by light and electron microscopy. Lipidosis‐like cellular alterations of considerable degrees were observed in lung, adrenal cortex and lymphatic tissue. Only mild lysosomal alterations were found in hepatocytes, adrenal medulla, retinal pigment epithelium and in peripheral and central nerve cell perikarya. The results show that zimelidine induces generalized lipidosis in rats although of mild degree when compared with some other amphiphilic cationic drugs.
Observations on the 2,4‐Dichlorophenoxyacetic Acid (2,4‐D) Excretion in the Goat
Authors: Örberg Jan
Published: July 2010

AbstractThe protein binding of 2,4‐D in goat plasma was studied by means of equilibrium dialysis and the renal excretion of 2,4‐D in three female goats by means of clearance methods. At low plasma levels of 2,4‐D (<20 μg/ml) about 97 per cent of 2,4‐D is bound to plasma proteins. The fraction of 2,4‐D bound to plasma proteins decreases with rising plasma 2,4‐D concentrations. A tubular secretion mechanism for 2,4‐D, with a Tmvalue of about 9 mg (40μmol)/min., is demonstrated. The contribution from the tubules to the 2,4‐D excreted per minute is greater than 97 per cent at a plasma 2,4‐D level of 10 μg/ml. At moderate and high plasma 2,4‐D concentrations (>40 μg/ml) the inulin clearance decreases with rising plasma 2,4‐D concentrations.
Copper‐induced GSH Depletion and Methaemoglobin Formation in Vitro in Erythrocytes of some Domestic Animals and Man. A Comparative Study
Authors: Sivertsen Tore
Published: July 2010

Abstract Reduced glutathione (GSH), per cent methaemoglobin and haemolysis were measured in physiologic saline suspensions of erythrocytes from sheep, goat, cattle, horse, swine and man; incubated for 24 hours at 37° with and without copper sulphate (0, 5 and 10 μg Cu/ml suspension). Formation of Heinz bodies was studied in similar experiments with sheep and swine cells only. Generally, GSH depletion developed first, followed by methaemoglobinemia and Heinz bodies, while haemolysis was limited. Both spontaneous and copper‐induced GSH depletion was slow in swine erythrocytes compared to other species. Copper‐induced methaemoglobin formation was less in cells from man and swine than from ruminants and horse. Furnishing the suspensions with 3 mg glucose/ml counteracted GSH and haemoglobin oxidation substantially in cells from all species except swine.
Pharmacokinetic Studies of 5‐Fluorouracil after Oral and Intravenous Administration in Man
Authors: Almersjö O. E. , Gustavsson B. G. , Regårdh C.‐G. , Wåhlén P.
Published: July 2010

Abstract The pharmacokinetic conditions for oral administration of 5‐fluorouracil (5‐FU) were investigated in 16 patients with malignant liver tumours. The concentration of 5‐FU in portal and systemic blood was determined by a microbiologic method every 10 min. during 2 hours after oral or intravenous administration of a standard dose of 250 mg 5‐FU (∼ 4 mg/kg b.wt.) or 15 mg 5‐FU/kg b.wt. The drug was rapidly absorbed after oral administration with peak values within 10–30 min. 25% of the lower and 40% of the higher oral dose reached the systemic circulation. The reduction of systemic bio‐availability was partly accomplished by a loss in the gastrointestinal tract and partly by extraction by the liver. The hepatic extraction ratio was calculated to 0.56 and 0.26 after the lower and the higher dose respectively indicating a saturable process. The availability of 5‐FU was significantly higher in portal blood than in systemic blood after oral administration. The opposite conditions were found after intravenous administration. Thus, oral administration of 5‐FU to patients with malignant liver tumours seems rational.
Combined Effects of Xylene and Alcohol on the Central Nervous System
Authors: Savolainen Kai
Published: July 2010

Abstract Ten healthy male students were exposed to m‐xylene alone at concentrations of about 6 and 11.5 μmol/l and given a single dose of alcohol (0.4 and 0.8 g/kg) prior to exposure. The effects of these xylene concentrations and alcohol doses, as well as the combined effects of the two xylene concentrations with the higher alcohol dose on psychophysiological functions, such as body balance and reaction time, were assessed. Xylene alone did not significantly impair these functions, although there was a tendency towards impairment by the exposure to the higher xylene concentration. The impairment caused by alcohol alone was dose‐dependent and exceeded that caused by xylene alone. The deleterious effects of xylene combined with alcohol were usually additive, although antagonism of alcohol effects on body balance by the higher xylene concentration was observed. The effects were pharmacodynamic rather than pharmacokinetic in nature.
Metabolism in Rats of Several Carboxylic Acid Derivatives Containing the 3,4‐Methylenedioxyphenyl Group
Authors: Klungsøyr Jarle , Scheline Ronald R.
Published: July 2010

Abstract: The metabolism of the 3,4‐methylenedioxy derivatives of mandelic acid (1), phenylacetic acid (2), benzoic acid (3), 3‐phenylpropionic acid (4) and cinnamic acid (5) was studied in rats. Following intragastric dosage (1 mmol/kg) the compounds and their metabolites were excreted in the urine within 24 hrs. Recoveries of roughly 85% were obtained. Except for compound (1) which was excreted to a large extent unchanged, glycine conjugates were the major urinary metabolites. Compound (2) formed 3,4‐methylenedioxyphenylacetylglycine whereas compounds (3), (4) and (5) were converted to 3,4‐methylenedioxybenzoylglycine. No evidence was found with any of the compounds for demethylenation and subsequent excretion of catecholic metabolites.
Liquid Chromatographic Method to Measure Thioridazine and its Active Metabolites in Plasma
Authors: Skinner T. , Gochnauer R. , Linnoila M.
Published: July 2010

Abstract: A liquid chromatographic method for the measurement of thioridazine, northioridazine, mesoridazine, and sulforidazine in biological samples is described. An alkaline aqueous to organic extraction procedure containing an evaporation step is used. The internal standard is 7‐methoxy‐chlorpromazine. The absolute limit of sensitivity is 5 ng of each drug in 1 ml of plasma. The coefficient of variation in routine use is of the order of 10 % both between runs, and within runs.
Alkylation of DNA by Organophosphorus Pesticides
Authors: Wooder M. F. , Wright A. S.
Published: July 2010

Methods for the detection of in vivo alkylation of nucleic acids are discussed. Alkylation of mammalian DNA at N‐7 of guanine provides the most sensitive and least equivocal evidence of methylation by an exogenous chemical or its metabolite. No 7‐methylguanine was detected in the combined DNA from the lungs, livers, hearts, brains, kidneys, testes and spleens from 20 rats exposed to 0.064 μg l‐1 of [Me‐14C]‐dichlorvos at a specific radioactivity of 113 Ci mol‐1 for 12 hrs.
Disparate Serum Thioridazine Concentrations: Liquid Chromatography versus Radioreceptor Assay
Authors: Linnoila Markku , Rosenblatt Jack E. , Jeste Dilip , Skinner Travis , Potter William Z. , Wyatt Richard Jed
Published: July 2010

Abstract: A radioceceptor and a liquid chromatographic assay quantitating serum thioridazine and its active metabolites yielded widely disparate results. The difference between the results of the two assays was relatively random. Contrary to earlier suggestions the radioreceptor assay may not be suitable for the measurement of all neuroleptics particularly when a common reference, such as chlorpromazine, is used.
Biphasic Effects of Inhaled Solvents on Human Equilibrium
Authors: Savolainen Kai , Riihimäki Vesa , Laine Arto
Published: July 2010

Abstract: Nine healthy male students were exposed for 4 hours at 6‐day intervals to atmospheric concentrations of m‐xylene (8.2 μmol/l; 200 p.p.m.) and 1,1,1‐trichloroethane (TCE) (8.2 and 16.4 μmol/l; 200 and 400 p.p.m.) and also to a combination of 8.2 μmol/l of xylene and of 16.4 μmol/l of TCE. The exposures took place during 6 consecutive weeks. Body sway was recorded with the subjects'eyes closed and open on each day with a strain gauge transducer platform prior to and during the exposures. For the average and for the maximal body sway, the ratio of the sway with the eyes closed to the sway with the eyes open was calculated for each recording. Xylene and TCE at 8.2 μmol/l in air tended to decrease the ratio, whereas the higher TCE concentration alone or in combination with xylene tended to have an opposite effect of the same magnitude. The results support the idea that TCE might exhibit a biphasic pattern of acute effects on the central vestibular system. Pharmacokinetic interactions between xylene and TCE were not observed.
Paroxetine: Pharmacokinetics and Cardiovascular Effects after Oral and Intravenous Single Doses in Man
Authors: Lund J. , Thayssen P. , Mengel H. , Pedersen O. L. , Kristensen C. B. , Gram L. F.
Published: July 2010

Abstract: Paroxetine kinetics and cardiovascular effects were studied in 4 healthy male subjects after single oral doses of 45 mg and after slow intravenous infusion of 23–28 mg. The plasma concentration/time curves could be described by a two‐compartment open model, but the estimates of the model parameters were relatively inaccurate after the oral test. Plasma half‐lives were longer after oral (19.8 hrs, S.D. 1.3 hrs) than after intravenous test (12.3 hrs, S.D. 3.8 hrs). Different methods of calculation of the systemic availability resulted in different values, most probably due to dose dependent kinetics. This is possibly related to saturated elimination kinetics during the first pass metabolism. Systolic time interval measurements showed that paroxetine causes a shortening of the electromechanical systole (QS2 corrected for heart rate) indicating a positive inotropic effect of the compound. Paroxetine also caused a reduction in heart rate and a moderate rise in systolic and diastolic blood pressure. After the intravenous dose some subjects experienced nausea and one subject a quite pronounced anxiety.
Biliary Excretion of Chromium in the Rat: A Role of Glutathione
Authors: Norseth Tor , Alexander Jan , Aaseth Jan , Langård Sverre
Published: July 2010

Abstract: The relative amount of chromium excreted in rat bile after injection of Cr‐III is much less than after injection of Cr‐VI, about 0.1% and from 6–8% during 5 hours respectively, for corresponding dose levels. The liver to bile ratio was 50–100 for Cr‐III injection, for Cr‐VI the ratio was 2–3. With doses up to 18 μmol Cr/kg, only Cr‐III was found in bile even after injection of Cr‐VI. Glutathione depletion of the liver with cyclohexene oxide decreased chromium excretion in bile. Such treatment also decreased the reduction of Cr‐VI to Cr‐III in the liver cell as only Cr‐VI was found in bile. A different distribution of Cr‐III in the liver dependent on whether derived from Cr‐VI or taken up by the liver as such must be assumed. Taking into account the usual low penetration of biological membranes by Cr‐III, a possible active transport mechanism or a specific diffusable Cr‐III compound must be postulated.
Absorption of NPH‐Insulin from Subcutaneous Tissue: A Methodological Study in Pigs
Authors: Deckert Torsten , Hansen Bruno , Kølendorf Klaus , Poulsen J. S. Dirch , Smith Mogens
Published: July 2010

Abstract: To elucidate the validity of the indirect method of following insulin absorption from the subcutaneous tissue, i.e. external counting of injected 125‐I insulin, the disappearance of 125‐I NPH insulin from subcutaneous tissue was measured by a biotelemetric method (external measurement of radioactivity) and by direct determination of radioactivity and insulin in subcutaneous tissue extracted one to 300 min. after injection of 8 units 125‐I NPH porcine insulin, 5 mm beneath the surface of the skin in 6 anaesthesized pigs. Furthermore. the appearance of insulin in arterial plasma was measured after inhibiting the endogenous insulin secretion of the pigs by epinephrine and propanolol. The disappearance of radioactivity measured continuously for 5 hours was of first order kinetics with t1/2 = 462 ± 36 min. (mean ± S.E.M.). The half‐life of the injected depot of radioactivity (t1/2) demonstrated a large intra‐ as well as interindividual variation as seen in diabetics. In tissue extracts a highly significant (2P < 0.001) correlation was found between radioactivity and insulin (r = 0.93), indicating the radioactivity to be representative of insulin. During gel chromatography on Sephadex G 50 M only one peak of radioactivity was seen in all tissue extracts. 300 min. afterNPH‐insulin injection, however, the specific radioactivity of insulin was significantly higher (2 P < 0.05) than in tissue extracts sampled one min. after NPH insulin injection, indicating a slight accumulation of non‐immunoreactive insulin degradation products. A fair correlation (r = 0.75, 2 P < 0.05) was seen between the disappearance of externally measured radioactivity or insulin from tissue extracts and the appearance of insulin in plasma. It is concluded that the insulin absorption coefficient is a relevant and biologically sensible expression of insulin absorption.
Glibenclamide‐induced Changes in Blood and Tissue Metabolite Levels in Fish
Authors: Khanna Neerja , Singh Tejendra
Published: July 2010

Abstract: Oral administration of a new antidiabetic drug, glibenclamide, in a freshwater fish, Puntius conchonius lead to notable changes in the blood and tissue metabolite levels. The drug caused significant hypoglycaemia and glycogen deposition in liver and skeletal muscles. Besides, the treated fish evinced marked hypocholesteraemia, hypoaminoacidaemia, a fall in FFA and phospholipid concentrations while the cholesterol content increased in the liver and kidneys. Most conspicuous change in various metabolite levels occurred at 8 hrs posttreatment, and restitution of normal values was achieved 24–48 hrs later. The drug appears to be endowed with remarkable insulinotropic property even in fishes.
The Influence of Some Thiols on Biliary Excretion of Methyl Mercury
Authors: Refsvik Tor
Published: July 2010

Abstract: N‐Acetylpenicillamine and thiola increased biliary excretion of methyl mercury and sulfhydryl right after administration. Cysteine increased excretion of methyl mercury in bile after a temporary decrease following administration. During the interval of decreased mercury excretion biliary excretion of cysteine passed through a maximum. This indicates the existence of a common factor of the excretory systems for cysteine and methyl mercury and illustrates that cysteine cannot carry methyl mercury from liver to bile. Relatively large proportions of unchanged thiola and N‐acetylpenicillamine were excreted in bile. Bile collected after administration of one of these compounds, in addition to thiola or N‐acetylpenicillamine, contained other methyl mercury carrying components not present in control bile. From the experiments undertaken it cannot be stated whether these components play any role in the increased excretion of methyl mercury in bile caused by thiola and N‐acetylpenicillamine. The mechanisms of increased biliary excretion of methyl mercury following administration of N‐acetylpenicillamine, thiola and cysteine are discussed.
Psychophysiological Measurements after Oral Atropine in Man
Authors: Seppälä Timo , Visakorpi Risto
Published: July 2010

Abstract: Eight healthy male volunteers received double‐blind and cross‐over placebo or atropine (0.85 or 1.7 mg). Various physiological, psychological and psychomotor measurements were made before a single oral dose and 1, 2 and 4 hrs after it. Typical peripheral antimuscarinic effects were found after atropine, maximally at 2–4 hrs. Atropine impaired flicker recognition, reaction time, short‐term memory, coordination, time anticipation and standing steadiness. The CNS‐impairment was maximal at 1 hr and dose‐related in most instances.
Effects of Cigarette Smoke on Rat Lung and Liver Ornithine Decarboxylase and Aryl Hydrocarbon Hydroxylase Activities and Lung Benzo(a)pyrene Metabolism
Authors: Raunio Hannu , Vähäkangas Kirsi , Saarni Hannu , Pelkonen Olavi
Published: July 2010

Abstract: The response of rat lung and liver ornithine decarboxylase (ODC) and aryl hydrocarbon hydroxylase (AHH) activities and lung benzo(a)pyrene (BP) metabolism was studied after exposing the rats to cigarette smoke. A close analysis of the time curves for ODC and AHH activities in rat lung and liver after a single exposure to cigarette smoke resulted in no clear correlation between the two parameters. Prolonged treatment (10 days) produced an increase in pulmonary ODC activity; hepatic ODC activity was unaffected. 10‐day treatment was ineffective in raising AHH activity above values observed after a single treatment. BP metabolism, as determined in isolated perfused lungs by the appearance of organic‐ and water‐soluble metabolites in the perfusion medium, the amount of covalently bound metabolites in lung tissue and the disappearance of unchanged 3‐H BP from the perfusate, was markedly increasead in response to cigarette smoke treatment. The data presented indicate that induction of AHH activity and increased metabolism of BP do not necessarily require a pre‐existing increase in ODC activity.
Activation of Phosphorylase by Anoxia and Dinitrophenol in Rabbit Colon Smooth Muscle: Relation to Release of Calcium from Mitochondria
Authors: Pettersson Göran
Published: July 2010

Abstract: The effect of anoxia or 2,4‐dinitrophenol (DNP) on the phosphorylase a activity and the calcium content in subcellular fractions from rabbit colon smooth muscle was studied. Anoxia for 15 min. as well as DNP (6.6 × 10−5 M) for 5 min. increased the phosphorylase a activity. The calcium content in the mitochondrial subfraction, prepared from the anoxic‐ or DNP‐treated intact muscle and determined by atomic absorption spectroscopy, was reduced. The calcium content in the nuclear and the microsomal fractions was not changed in preparations with a normal Ca‐content. When the muscle was incubated for 60 min. in a Ca2+‐free medium containing 2.0 mM EGTA, the calcium content in the mitochondrial fraction was reduced to 38 % of the control. This calcium level was still further reduced and the phosphorylase a activity was increased by DNP in this “Ca‐poor” muscle. In these preparations the Ca‐content of the microsomal + supernatant fraction increased. Only when the muscle was incubated, initially, in an anoxic medium containing 0.1 mM Ca2+ for 120 min. and, subsequently, in an oxygenated medium containing 0.1 mM Ca2+ for 20 min., DNP failed to activate phosphorylase and to decrease the calcium content in the mitochondrial fraction. These results indicate that mitochondrial Ca2+ release is one of the regulatory factors of the anoxic‐induced glycogenolysis.
Changes in Steady State Digoxin Pharmacokinetics during Quinidine Therapy in Cardiac Patients: Influence of Plasma Quinidine Concentration
Authors: Pedersen Knud Erik , Christiansen Bent Dorff , Klitgaard Niels Anders , Nielsen‐Kudsk Folmer
Published: July 2010

Abstract: In seven cardiac patients on long‐term digoxin therapy, digoxin kinetics were investigated — in the absence and presence of quinidine — after simultaneous administration of an oral digoxin dose and an intravenous 3H‐digoxin bolus injection. From 3H‐digoxin data quinidine was found to decrease both renal (from 1.19 ±0.35 to 0.86 ±0.21 ml/min./kg) (P<0.02) and extrarenal clearances of digoxin (from 0.85 ±0.24 to 0.49±0.23 ml/min./kg) (P<0.02), and to diminish the steady state distribution volume of the drug (from 6.78 ± 1.23 to 5.63 ± 1.64 l/kg) (P<0.02). Plasma half‐life increased from 51.5 ±5.4 to 64.4±14.8 hrs (P<0.05), while urinary excretion half‐life increased from 54.4±3.9 to 78.5± 14.1 hrs (P<0.01). Pharmacokinetic parameters derived from plasma and urinary digoxin data showed similar changes during quinidine therapy. Reduction in renal 3H‐digoxin clearance occurred at subtherapeutic plasma quinidine levels and was independent of plasma quinidine, whereas reductions in extrarenal 3H‐digoxin clearance and 3H‐digoxin distribution volume were positively correlated to plasma quinidine concentrations (P<0.05).
Lack of Functional Influence by Prenalterol through α1‐Adrenoceptors in Rat Myocardium
Authors: Aass Halfdan , Hedberg Anders , Skomedal Tor , Carlsson Enar , Osnes Jan‐Bjørn
Published: July 2010

Abstract: Some of the cardiac properties of the partial β‐agonist prenalterol may indicate a contribution from α1‐adrenergic stimulation. We therefore studied whether prenalterol interacted with α1‐adrenoceptors in rat myocardium. Combination with propranolol did not reveal an α1‐adrenergic inotropic effect of prenalterol in papillary muscles. Neither did prenalterol block the α1‐adrenergic response to phenylephrine. In myocardial cells, prenalterol inhibited 3H‐prazosin binding to α1‐adrenoceptors only at very high concentrations. Prenalterol thus exhibited no functionally important interactions with α1‐adrenoceptors in myocardium, and its properties cannot be accounted for in terms of contribution from α1‐adrenergic effects.
Decrease of Serum Angiotensin Converting Enzyme Activity after Discontinuation of Captopril Treatment
Authors: Forslund Terje , Tikkanen Ilkka , Fyhrquist Frej
Published: July 2010

Abstract: Serum ACE activity increased as expected about three‐fold following six weeks of captopril (30 mg/kg/day) treatment in Wistar rats (n=9). The effect on serum and lung ACE activity and concentration, respectively, was studied after captopril discontinuation. Serum ACE activity was measured at start and 3, 6, and 12 days after captopril withdrawal. The approximal half‐life of serum ACE activity was 72 hours as judged from the decrease rate after stimulated ACE biosynthesis induced by captopril. No differences in lung plasma membranes and lung homogenate ACE concentrations between treated and untreated rats were observed 12 days after discontinuation of captopril treatment. Serum ACE activity remained unchanged in the control rats (n=9). We conclude that induction of ACE biosynthesis in the rat is reversible after withdrawal of captopril.
The Mechanism of Biliary Excretion of Methyl Mercury: Studies with Methylthiols
Authors: Refsvik Tor
Published: July 2010

Abstract: The S‐methylated derivatives of N‐acetylpenicillamine, thiola and cysteine as well as methyl iodide decreased biliary excretion of methyl mercury markedly. Excretion of sulfhydryl in bile was not influenced by S‐methyl‐cysteine, S‐methylthiola, S‐methyl‐N‐acetylpenicillamine or a low dose of methyliodide (0.5 mmol/kg body weight). This seems to indicate that coupling of methyl mercury to glutathione in the liver before biliary excretion is a glutathione S‐transferase dependent reaction. It also indicates that the methylthiols tested, or metabolites of these compounds are likely to be inhibitors of S‐transferase. The effect of S‐methylcysteine and low doses of methyl iodide probably reflects glutathione S‐transferase inhibition as both compounds are metabolized to the S‐transferase inhibitor S‐methylglutathione in the liver. A higher dose of methyl iodide (1 mmol/kg body weight) seems to deplete the liver of reduced glutathione through S‐methylation as illustrated by decreased biliary excretion of sulfhydryl. S‐methylthiola and S‐methyl‐N‐acetylpenicillamine are metabolized in the liver to unknown components which are excreted in bile. Whether S‐methylthiola and S‐methyl‐N‐acetylpenicillamine are inhibitors of S‐transferase themselves or cause inhibition through metabolites cannot be stated from the present investigation.
Methodological Aspects of Acute Toxicity Testing Particularly LD50 Determinations Present use in Development of New Drugs
Authors: Fowler J.S.L. , Rutty D.A.
Published: July 2010

Abstract It is essential to have an adequate understanding of the acute toxic effects of a new drug. It may not be necessary however to blindly follow the full classical median lethal assay on every occasion.

The LD50 was developed to obtain the maximum accuracy from a modest experimental size. The objective of the study and the limitations of the assay should not be overlooked however and undue precision should not be sought.

Methodological aspects including species and maximum and minimum doses will be discussed.

Other methods and approaches to acute toxicity will be recommended with a more broad approach to acute toxicity than lethality alone.
Predictive Acute Toxicity Tests With Pesticides.
Authors: Brown V. K.
Published: July 2010

Abstract By definition pesticides are biocidal products and this implies a probability that pesticides may be acutely toxic to species other than the designated target species.

The ways in which pesticides are manufactured, formulated, packaged, distributed and used necessitates a potential for the exposure of non‐target species although the technology exists to minimize adventitious exposure. The occurrence of deliberate exposure of non‐target species due to the misuse of pesticides is known to happen.

The array of predictive acute toxicity tests carried out on pesticides and involving the use of laboratory animals can be justified as providing data on which hazard assessment can be based. This paper addresses the justification and rationale of this statement.
The use of acute toxicity data in poison information centres.
Authors: Werner B.
Published: July 2010

Abstract Of the various animal test data the poison information centres consider the eye and skin irritation tests to be useful and the findings transferreble to man for evaluation of acute exposure risks.

The LD50 and LC50 data are considered of doubtful value and even to involve some risks. Presented as uncommented figures, especially if placed alongside physical data on a chemical substance, they are given a nimbus of exactness that they are not entitled to because of the known reasons of species differences etc. LD50‐s are mortality data but what the poison information centres need are morbidity data. Doses lower than LD50 are as TD‐s therefore more of interest, provided they are given with a detailed description of the developing intoxication symptoms, preferrably also with information on the steepness of the dose‐symptoms curve. The facilities today to prevent death due to acute poisonings place the residual symptoms at survival more in the centre of interest and responsibility. Careful postmortems of the test animals are therefore also needed. Although examinations may have been performed on the animals killed by the LD50 dose they might have died too early for a late organ damage to appear (e.g. in paraquat poisoning the animal may die in kidney insufficiency which comes earlier than the obliteration of the bronchioli respiratorii) or the killing factor may be another than the one involved in the residual symptoms (e.g. CO‐poisoning, where COHb is the life‐limiting factor in gross exposure but does not seem to be related to the severe late CNS symptoms).

When rating the toxicity of closely related but different compounds LD50 has some value.

Suggestions: Symptoms developing at different TD‐s should be presented. Organs should be examined macro‐ and microscopically (had this been done the vacuoles in the CNS might have been seen early in the animal testing of hexachlorophene and human poisonings thereby prevented). The human poisoning cases — now not used to the extent they could be for drawing information regarding the poisoning — should be studied much more in detail and the information from different countries pooled. Poison information centres could act as a network.

LDlow and TDlow in man would then be better and earlier known. The clinicians should, however, then be given better facilities of collaboration with toxicological laboratories, to make it possible to widen the scope of investigations, which now often must be limited to the need of the individual case. Starting from clinical findings animal tests — as is already the practice — should be done to deepen the understanding of mechanisms. Cultures of surviving cells could in some situations add important information and will probably be increasingly used.
Embryotoxic Effects of Acrolein, Methacrylates, Guanidines and Resorcinol on Three Day Chicken Embryos
Authors: Korhonen Aila , Hemminki Kari , Vainio Harri
Published: July 2010

Abstract: Acrolein, four methacrylates, two guanidine compounds and resorcinol were tested for embryotoxicity on three day chicken embryos. The most potent chemical was acrolein, with the ED50 0.05 μmol per egg for the total effect, including deaths and malformations. The substances next in potency were N,N'‐di‐o‐tolyl‐guanidine and N,N‐diphenylguanidine, with ED50 values 0.17 and 0.20 μmol per egg, respectively. Resorcinol and the methacrylates had ED50 values ranging from 2.4 to 22.0 μmol per egg. Acrolein, diphenylguanidine, tetrahydrofururylmethacrylate and trimethylolpropanetrimethacrylate caused the largest amounts of malformed embryos.
Effects of Certain Mono‐, Di‐ and Trivalent Metal Cations on the K+‐stimulated p‐Nitrophenyl Phosphatase in Rat Brain
Authors: Bansal S. K. , Murthy R. C. , Chandra S. V.
Published: July 2010

Abstract: The effects of certain monovalent (Ag+1 and Li+1), divalent (Hg+2, Cu+2, Zn+2, Co+2, Fe+2, Pb+2, Mn+2, Sn+2, Ni+2, and Se+2) and trivalent (Fe+3, As+3, and Al+3) metals on a mitochondrial preparation of K+‐stimulated‐p‐nitrophenyl phosphatase (K+‐PNPPase) from rat brain were studied. Except for salts of Ni+2, Se+2 and Li+1, which irrespective of concentration failed to produce 50% inhibition, all of the metals examined were found to be potent inhibitors of the enzyme with 150 values of 0.24 μM for Ag+1 among the monovalent, 0.70, 30, 37, 38, 47, 60, 62, 490 and 850μM for Hg+2, Cu+2, Cd+2, Zn+2, Co+2, Fe+2, Pb+2, Mn+2 and Sn+2, respectively, among the divalents and 100, 550 and 870 μM for Fe+3, As+3, and AL+3 respectively, among the trivalents. Salts of silver and mercury were the most toxic for this enzyme. All metals showed concentration dependent inhibition except lithium. The order of their potency was Ag+1> Hg+2> Cu+2> Cd+2> Zn+2> Co+2> Fe+2> Pb+2> Fe+3> Mn+2> As+3> Sn+2> Al+3> Ni+2> Se+2> Li+1.
Gentamicin‐induced Hypercalciuria in the Rat
Authors: Chahwala Suresh B. , Harpur Ernest S.
Published: July 2010

Abstract: A study was made of the effects of gentamicin (40 mg/kg/day for 7 days) on the excretion of sodium, potassium, calcium and magnesium in the urine of rats. Volume of urine, protein excretion and the urinary activities of the enzymes alanine aminopeptidase, lactate dehydrogenase and N‐acetyl‐β‐glucosaminidase were also monitored. There were no significant changes in the excretion of sodium or potassium and the excretion of magnesium was too variable to permit a meaningful interpretation of changes in its excretion. Significant changes occurred in the excretion of calcium and protein and in the 24 hr urine osmolarity. The earliest of these changes, on day 4, was an increase in calcium excretion (P<0.01) which progressed until the drug was stopped and persisted throughout the 5 follow‐up days. The increase in protein excretion was significant (P<0.01) by day 5 and the decrease in osmolarity (P<0.01) by day 6. These changes were preceded, on day 1, by a significant (P<0.001) rise in the activities in urine of all three enzymes. This early enzymuria suggests that considerable perturbation of cell integrity occurred before the increase in calcium excretion. Further studies are required to elucidate what role, if any, the loss of calcium plays in the genesis of tubular cell injury.
Trichloroethylene: Further Studies of the Effects on Body and Organ Weights and Plasma Butyrylcholinesterase Activity in Mice
Authors: Kjellstrand P. , Holmquist B. , Alm P. , Kanje M. , Romare S. , Jonsson I. , Månsson L. , Bjerkemo M.
Published: July 2010

Abstract: The effects of continuous and intermittent inhalation of trichloroethylene (TCE) were studied in male and female mice. Plasma butyrylcholinesterase (BuChE) activity, body, liver, kidney and spleen weights were measured. The liver was studied histologically and motor activity measured with doppler radar. Continuous TCE‐exposure (37–300 p.p.m.) increased plasma BuChE activity in the males in a time and concentration dependent manner. After 30 days at 37 p.p.m. the increase was about 25%. Exposure to 300 p.p.m. for 30 days increased the activity three times. BuChE activity in females was only slightly influenced even at 300 p.p.m. Liver weight was increased in a time and concentration dependent manner in both sexes. In animals continuously exposed for 30 days to 300 p.p.m., liver weight was roughly twice that of the air‐exposed controls. Morphological changes were observed in the liver of TCE‐exposed animals. Above 150 p.p.m. kidney weight in both sexes was significantly increased. This effect was more pronounced in the males than in the females. Spleen weight was not influenced by the exposure. Body weight increase was slightly lower in exposed animals. Plasma BuChE activity and liver weight returned to normal when exposure was terminated. Intermittent exposure to short pulses of high concentration of TCE had roughly the same effect on BuChE, body and organ weights as continuous exposure to the same time‐weighted average. Motor activity was affected by the intermittent exposure schedules. At 900 p.p.m. decrease in activity was observed. At 3600 p.p.m. motor activity was considerably increased.
Cytotoxicity of Sodium Monofluorophosphate
Authors: Holland Roy I.
Published: July 2010

Abstract: Sodium monofluorophosphate (MFP) was cytotoxic to fluoride‐sensitive cells in culture, but not to fluoride‐resistant cells, indicating that the cytotoxicity of MFP is due to fluoride ions, a hydrolysis product of MFP.
A Method for Simultaneous Epicardial Monophasic Action Potential Recordings from the Dog Heartin Situ
Authors: Platou Eivind S. , Steinnes Knut , Refsum Helge
Published: July 2010

Abstract:In order to record epicardial monophasic action potentials (MAP) simultaneously from different regions of intact beating hearts, we developed a tripodal suction electrode device (total weight 1.5 g, distance between the flexible silicone legs 25 mm) which we tested in pentobarbital anaesthetized open chest dogs. The device was easy to apply and gave stable and reproducible recordings. Repolarization times for epicardial left ventricular and endocardial right ventricular MAPs correlated well (r = 0.97, P<0.001). There was no correlation between MAP amplitude and repolarization times. The β1‐adrenergic agonist prenalterol decreased MAP duration, while the new class III antiarrhythmic drug melperone increased MAP duration. Mild ischaemia effected MAP prolongation and severe ischaemia MAP shortening, compared to simultaneous recordings from non‐ischaemic ventricular regions. We conclude that the new tripodal suction electrode is a simple device for simultaneous recording of multiple MAPs. The method should be suitable for studies of electrophysiological effects of drugs and other interventions in intact beating hearts.
Sodium N‐Methyl‐D‐glucamine Dithiocarbamate and Cadmium Intoxication
Authors: Shinobu Leslie A. , Jones Shirley G. , Jones Mark M.
Published: July 2010

Abstract: The sodium and ammonium salts of N‐methyl‐D‐glucamine dithiocarbamate were prepared and their usefulness as antidotes for cadmium intoxication investigated. This chelating agent was found to be effective in both acute and repeated exposure cadmium poisoning. A single intraperitoneal injection of sodium N‐methyl‐D‐glucamine dithiocarbamate (NaNMG‐DTC), administered at a level greater than 1.1 mmol/kg body weight, protects against a normally lethal (>95%) dose of cadmium chloride (10 mg CdCl2/kg body weight) and results in a subsequent dose‐dependent decrease in the liver and kidney burdens of cadmium ion. In repeated exposure cadmium intoxication, repeated administration of NaNMG‐DTC can result in substantial reductions in both the kidney (71%) and the liver (40%) levels of cadmium. The LD50 of the compound was not determined, but single injections of 26.6 mmol/kg body weight (injectate volume 1.0 ml) are well tolerated in mice.
Absorption of Selenite in the Rat Small Intestine: Interactions with Glutathione
Authors: Anundi Irene , Hógberg Johan , Ståhl Annika
Published: July 2010

Abstract: Incubation of isolated rat intestinal epithelial cells with selenite resulted in a rapid decrease of intracellular glutathione (GSH) and about 5 nmol of Se (added as 75Se labelled selenite, 50 μM) was accumulated per 106 cells during 20 min. Addition of exogenous GSH enhanced cellular accumulation of Se, while the β‐glutamyl transferase inhibitor, serine‐borate, decreased uptake. The added exogenous GSH was rapidly consumed (oxidized) by selenite. Depletion of GSH by diethylmaleate (DEM) inhibited selenite uptake both in in situ isolated intestinal loop, everted gut sacs and in isolated intestinal cells. The findings indicate that both intracellular and extracellular GSH, and β‐glutamyltransferase, play a role in the absorption of selenite in the intestine.
Sarin Poisoning in Guinea Pigs Compared to Reactivation of Acetylcholinesterase in Vitro as a Basis for Therapy
Authors: Hopff Wolfgang H. , Riggio Gaetano , Waser Peter G.
Published: July 2010

Abstract: Contrary to the large number of publications dealing with treatment of organophosphate poisoning in a variety of animal species, there is no logic reason in the preference of one species, for this purpose. Guinea pigs were reported to respond better to treatment by oximes, than mice and rats. However, in the analysis of data on the effect of obidoxim and atropine or benactyzine on sarin poisoning it is demonstrated, that guinea pigs do not respond differently from mice and rats. Subcutaneous LD50's of sarin in mice ranged from 0.06 to 0.207 mg/kg, and those of guinea pigs from 0.04 to 0.112 mg/kg. The difference in the LD50's may be related to the different susceptibility of various animal species. The importance of “in vivo” dosage, mode of application, kinetics of antagonists, in correlation to the ability to reactivate “in vitro” is discussed.
Dietary Arachidonic Acid Protects Mice against the Fatty Liver Induced by a High Fat Diet and by Ethanol
Authors: Karpe Fredrik , Wejde Johan , Änggård Erik
Published: July 2010

Abstract: Five groups of NMRI mice were fed ethanol or sucrose in a nutritionally adequate liquid diet for 9 days. The dietary fat consisted of olive oil with the fatty acid composition 18:1 77%, 18:2 10%, 18:0 and 16:0 12%. The ethanol treated groups received 5% w/v ethanol (E) or isocaloric sucrose (S). Two groups (S‐ and E‐) received the diet without supplement. In two groups (S+ and E +) 7% of the fat was exchanged for arachidonic acid (20:4). In a fifth group (IE +) treated with ethanol and arachidonic acid the diet also contained indomethacin (10 mg/1). The mean intake of ethanol was about 20 g/kg/day. After 9 days animals were killed and liver lipids analyzed after Folch extraction. The post mortem accumulation of prostaglandin E2 in the kidney was measured by GC‐MS. Dietary 20:4 was found to protect mice against fatty liver caused both by a high fat diet alone and in combination with ethanol. The liver triglycerides were 30.7 + 4.3 (S ‐), 46.1+6.9 (E ‐), 6.8 + 0.4 (S +) and 19.4 ±1.8 (E +). Prostaglandin levels in the kidney were depressed by ethanol treatment. Indomethacin gave variable degrees of PG synthesis inhibition. The degree of liver triglyceride accumulation in the IE+ group was inversely propotional to the degree of PG synthesis. The data suggest a role for liver 20:4 cyclooxyganase metabolites in fatty liver caused by high fat diets and ethanol.
Antimuscarinic Activity of Oxybutynin in the Human Plasma Quantitated by a Radioreceptor Assay
Authors: Aaltonen L. , Allonen H. , Iisalo E. , Juhakoski A. , Kleimola T. , Sellman R.
Published: July 2010

Abstract: The antimuscarinic activity of oxybutynin was measured as oxybutynin equivalents by a radioreceptor assay (RRA). The activity was studied in plasma samples of five volunteers after a single oral dose (10 mg) or after a single intravenous dose (28 μg/kg) of oxybutynin hydrochloride. The results were compared to the concentrations of the drug measured by gas liquid chromatography (GLC). Following oral administration, the maximum concentration measured by RRA was significantly higher (706 nmol/1) than that by GLC (38 nmol/1). In contrast, equal concentrations were measured after intravenous administration by both methods. Metabolites with antimuscarinic activity are possibly formed through first‐pass metabolism after orally administered oxybutynin. The total antimuscarinic activity of oxybutynin and its metabolites are measured by RRA, but only the parent drug by GLC.
Forskolin‐stimulated Adenylate Cyclase Activity in Rat Cerebral Cortex Following Chronic Treatment with Psychotropic Drugs
Authors: Andersen P. H. , Klysner R. , Geisler A.
Published: July 2010

Abstract: Rats were treated with lithium, imipramine, reserpine, and lithium combined with imipramine or reserpine. Lithium was given in the diet (40 mmol/kg) resulting in a serum‐Li+ level of 0.5–0.6 mmol/1. Other drugs were dissolved in 0.9% saline and given intraperitoneally once or twice daily. After 3 weeks of treatment, forskolin‐stimulated adenylate cyclase activity was measured in cerebral cortex homogenates. Reserpine did not affect the forskolin stimulation, while both imipramine and lithium caused a decrease in this activity. The combined treatments lithium‐imipramine and lithium‐reserpine also exhibited a clear decrease in forskolin stimulation, but the effect of concomitant lithium and imipramine treatment did not differ from the effect seen after any of the treatments alone. The unstimulated activity was unaltered by all treatments. The inhibition of lithium and imipramine on the forskolin stimulation indicates an interference of these two drugs with the forskolin‐mediated activation of the adenylate cyclase.