bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Chlorhexidine on Some Biochemical Parameters of Rat Liver Microsomes
Authors: Cbristensen Flemming , Jensen Jørn Erik
Published: July 2010

The effect of chlorhexidine (Chx) on some biochemical parameters of rat liver microsomes was studied. At concentrations of Chx above 100 μM a precipitate was formed with the microsomes and the precipitate was maximal above 200 μM. The major part of the microsomal proteins was also precipitated at concentrations of Chx exceeding 200 μM. When the concentration of Chx was higher than 75 μM cytochrome P‐450 was partly precipitated and partly converted to cytochrome P‐420. A concentration dependent inhibition of p‐nitro‐anisole‐O‐demethylase was observed, the activity being almost totally inhibited at 600 μM. The activity of microsomal glucose‐6‐phosphatase was markedly enhanced (70‐80 %) by Chx at concentrations above 75 μM although the activity of the enzyme was precipitated by Chx. The microsomes bound increasing amounts of Chx with increasing concentrations of the compound until about 1000 μM at which concentration the binding was maximal.
Uptake of 14C‐Neostigmine in Rat Striated Muscles
Authors: Christensen Chr. Broen , Helleberg Lars
Published: July 2010

The uptake of 14C‐neostigmine in striated muscles was studied after intravenous injection into rats and in the isolated rat diaphragm. 120 minutes after the intravenous injection of 14C‐neostigmine (100 μg/kg) the 14C‐concentration in the quadriceps, sternomastoid and intercostal muscles was 1/3‐1/2 of the concentration in the plasma, whereas the 14C‐concentration in the diaphragm was about double the concentration in the plasma. After continuous intravenous infusion of 14C‐neostigmine the distribution pattern was the same as after a single injection. Paper chromatography showed that the radioactivity in the diaphragm was due partly to unchanged neostigmine, partly to a metabolite. In the isolated diaphragm unchanced 14C‐neostigmine accumulates against an apparant concentration gradient. The uptake is partly saturable and energy‐dependent. It is suggested that intracellular accumulation of neostigmine and/or its metabolites may be causally related to the respiratory failure following overdosage of neostigmine.
Effect of Manganese on Enzymes in Rat Brain
Authors: Sitaramayya A. , Nagar Neeti , Chandra Satya V.
Published: July 2010

Rats were given MnCl2.4H2O (8 mg/kg) intraperitoneally daily for 120 days, and then sacrificed by decapitation. The brain was removed and dissected into three regions; cerebral cortex, cerebellum and remainder of the brain. Enzymic studies were conducted in these regions and compared with control animals. The activities of acetyl choline esterase and adenosine deaminase were significantly reduced in all the three regions. The activity of monoamine oxidase was increased in the cerebellum while the activity of guanine deaminase decreased in the cerebellum and remainder of the brain. The analysis of the results allows no overall generalization in enzymic alterations induced by manganese chloride in the three regions of the rat brain.
Micro‐determination with Automatic Registration of CO2 in Biological Experiments
Authors: Holm‐Jensen Ib
Published: July 2010

A procedure is described by means of which the rates of CO2 elimination from small animals, from seeds, or from samples of surviving tissues, can be determined and registered automatically by a strip‐chart recorder. The specimen under study is placed in a closed‐circuit arrangement in which CO2 is absorbed in a Sr(OH)2 solution. The registration of the CO2 liberation is based on the change in the electrical conductivity of the Sr(OH)2 solution which occurs during the CO2 absorption. The proposed arrangement is suitable for the determination of a quantity of CO2 up to 5 μM. When this amount of CO2 is liberated in less than one hour, an accuracy of ± 0.5 per cent can easily be obtained.
Effects of Psychotropic Drugs on the Incorporation of Glucose‐14C into Amino Acids of the Rat Brain
Authors: Edelfors Sven
Published: July 2010

Abstract: The effects of chlorpromazine, 25 mg/kg subcutaneously, nialamide, 50 mg/kg intraperitoneally, and imipramine, 100 mg/kg intraperitoneally, respectively, on the glucose and amino acid metabolism of the central nervous system of the rat were examined. Thirty minutes after the injection of U‐14C‐D‐glucose the total amount and specific activity of the amino acids, aspartic acid, glutamic acid, glutamine, alanine, and γ‐amino butyric acid from the brain were determined. The total amount and the specific activity of blood glucose were similarly determined. With imipramine the study was extended to include 5, 15, 30, 45, and 90 min. after injection of U‐14C‐D‐glucose. Imipramine reduced the glucose concentration, but brought about an increase in the specific activity of glucose. Chlorpromazine reduced the specific activity of the amino acid tested. Nialamide increased the specific activity of aspartic acid and γ‐amino butyric acid. Imipramine increased the specific activity of the amino acids tested by 100–200 per cent. At the same time a decrease in the total quantity was observed.
Activation and Inactivation of Membrane‐Bound UDP‐glucuronosyltransferase by Organic Solvents in Vitro
Authors: Vainio Harri
Published: July 2010

Abstract: Organic solvents such as chloroform, acetone, ethyl ether or n‐hexane, are all able to enhance the measurable UDP‐glucuronosyltransferase activity when added in vitro to the microsomal suspension. The aliphatic alcohols, methanol, ethanol, or butanol were, however, unable to activate the microsomal enzyme but caused instead an inhibition of the UDP‐glucuronosyltransferase. The inhibitory action increased with the length of the alkyl chain.
Elimination of Intravenously Injected 125I‐Toluidine Blue into Rabbits
Authors: Nermann Eldar
Published: July 2010

Abstract: The elimination of intravenously injected 125I‐toluidine blue was studied in rabbits. Within 5 minutes after the injection, approximately 80% of the dye had been metabolized, being present in the plasma and urine in a colourless state. As much as 99% of the label was recovered in the urine and faeces within 3 days. It is therefore assumed that in future clinical parathyroid scintigraphy, the absorbed radiation dose with radioiodinated dye will be smaller than with 75Se‐selenomethionine, the currently used radiopharmaceutic compound for the parathyroids.
On the Immunological Histamine Release from Guinea‐pig Lung and its Inhibition by Isoprenaline
Authors: Sörenby Lars
Published: July 2010

Abstract: Some experimental conditions in connection with the ovalbumin‐stimulated release of histamine from the actively sensitized guinea‐pig lung in vitro and the influence of isoprenaline on this release have been studied. At 37° the release process was completed within 15 minutes. Incubation did not change the tissue content of histamine extractable by boiling. Isoprenaline, 2×10‐8 M, inhibited 50–60 per cent of the control release of histamine. The effect was fully blocked by propranolol, 10‐7 M. The inhibitory effect of isoprenaline was found to be restricted to the calcium‐dependent release of histamine. The preincubation time of isoprenaline was not critical. An increase in the dose of antigen did not impair the ability of isoprenaline to inhibit the release of histamine.
Changes of Glomerular Filtration Rate and Renal Plasma Flow Following Intravenous Bumetanide in Organic Heart Disease
Authors: Bollerup Anne Cathrine , Hesse Birger , Sigurd Bjarne
Published: July 2010

Abstract: The renal effects of bumetanide, a new potent diuretic, were studied in ten patients with latent congestive heart failure. Following the intravenous administration of 3 mg bumetanide the glomerular filtration rate (GFR) and renal plasma flow (RPF) showed initial, statistically significant increments over control values, and subsequent statistically significant reductions. This biphasic pattern was unrelated to the diuresis and natriuresis which were sustained for a longer period. The pathophysiological mechanisms involved in the changes of GFR and RPF are discussed and it is suggested that the initial rise in GFR and RPF is primarily due to a vasodilating effect of bumetanide.
Tissue Concentrations of Digoxin in an Autopsy Material
Authors: Karjalainen Jouko , Ojala Kaarina , Reissell Pentti
Published: July 2010

Abstract: The tissue concentrations of digoxin were measured in 13 cadavers who before death had been on the maintenance digoxin therapy. Tissue samples were taken from 5 different parts of the heart, from skeletal muscle, liver and kidney. Digoxin was extracted by dichlormethane and measured by radioimmunoassay. Whole blood digoxin was measured by the same method. The appropriate recovery studies showed good extraction. The highest heart digoxin concentration was found in the septal muscle (mean 132 ± S. D. 65 ng/g) and the lowest in the left auricle (43 ± 26 ng/g). The heart concentrations were in good correlation with the whole blood concentration — the best correlation was found with the ventricular muscle (r = 0.86). The skeletal muscle concentration was about 15 % of the heart concentration (20 ± 13 ng/g) and the correlation with the whole blood was poorer (r = 0.54). The kidney concentration (123 ± 65 ng/g) was approximately the same as that of the heart and the liver concentration was 68 ± 51 ng/g. The results indicate a linear correlation between blood and heart.
The Effect of Chlorhexidine on some Biochemical Parameters of Rat Liver Mitochondria
Authors: Christensen Flemming , Bleeg Henry S. , Jensen Jørn Erik
Published: July 2010

Abstract: Chlorhexidine (CHX) binds to isolated rat liver mitochondria with a saturation of binding at 900 nmol per mg protein. The binding is completed within 20 sec. and the binding does not render the mitochondria capable of sedimentation at 600 X g. A slight solubilization of mitochondrial proteins is obtained with 100 μM CHX, whereas higher concentrations of CHX (250 μM) result in an increase in the amount of protein sedimenting at 15,000 X g. Low concentrations of CHX (25 μM) have an uncouplinglike effect on the mitochondrial electron transport system. Inhibition of respiration is observed with 100 μM CHX. The activity of ATP‐ase is slightly stimulated with 15 μM CHX and inhibited 50% with 100 μM CHX. Membrane‐bound mitochondrial enzymes, e. g. succinate: cytochrome c reductase, proline oxidase and kynurenine hydroxylase are inhibited by CHX at 70 μM, 200 μM and 1 mM CHX respectively. Malate dehydrogenase (a mitochondrial matrix enzyme) is solubilized by CHX. At 25 μM CHX 87% of the activity is liberated from the mitochondrial matrix. The soluble enzyme is not inhibited by higher concentrations of CHX. The results are tentatively explained as being due to effects of binding of CHX to the mitochondrial membranes. Chlorhexidine is considered to be an amphipathic substance being capable of penetrating the non‐polar regions of phospholipid bilayers and at the same time being able to bind as a bication to phosphate groups in the phospholipids.
Mammary Excretion of Digoxin in Goats
Authors: Rasmussen Folke , Nawaz M. , Steiness Eva
Published: July 2010

Abstract: The binding of digoxin to proteins in plasma and milk was about 20% lower after the addition of the drug to plasma and milk (in vitro) than its binding in plasma and milk from animals administered digoxin parenterally. The mammary excretion of digoxin was examined in the experiments on goats. The concentration of non‐protein‐bound digoxin in milk was slightly lower than the concentration of non‐protein‐bound in plasma suggesting a passive diffusion. The amount of digoxin excreted with the milk per day should be far below the dose usually recommended for a newborn child.
The Effect of Glycerol on the Lactate Metabolism in the Perfused Rat Liver
Authors: Olsen Christian
Published: July 2010

Abstract: The effect of glycerol on the lactate metabolism was studied on the perfused rat liver. Addition of glycerol to the perfusion medium caused a significant output of lactate and uptake of pyruvate. The lactate/pyruvate‐ and β‐hydroxybutyrate/acetoacetate ratios rose indicating an effect of glycerol on the cytoplasmic and mitochondrial redox potentials which became more reduced. The output of lactate by the liver may be a result of the reduction in the redox level induced by the oxidation of glycerol.
Cumulation in Cerebrospinal Fluid of the N‐desmethyl Metabolite after Long‐term Treatment with Diazepam in Man
Authors: Hendel Jørn
Published: July 2010

Abstract: Thirteen patients were given 10 mg diazepam intramuscularly 12 hrs and 1 hr before spinal puncture. Plasma and cerebrospinal fluid concentrations of diazepam and the main metabolite N‐desmethyldiazepam were determined simultaneously in the plasma and the cerebrospinal fluid. Five patients treated with diazepam over several months showed a significantly higher N‐desmethyldiazepam ratio (cerebrospinal fluid/plasma) than eight patients not previously treated with diazepam. This indicates a cumulation of this psychoactive metabolite in the brain of man during long term treatment with diazepam.
Effect of Treatment of Rats with Some Chemical Carcinogens on the Stimulatory Effect of Adrenaline on Cyclic AMP Accumulation in Liver Slices
Authors: Christoffersen Thoralf
Published: July 2010

Abstract: The stimulatory effect of adrenaline on the formation of cyclic AMP in rat liver, measured as accumulation of the nucleotide in slices in vitro in the presence of theophylline, was found to be increased after treatment of the animals with various carcinogens for 4–8 weeks. For the compounds tested, the order of effectiveness in this respect was 2‐acetylaminofluorene > 3′‐methyl‐4‐dimethylaminoazobenzene > 4‐dimethylaminoazobenzene > 2′‐methyl‐4‐dimethyl‐aminoazobenzene; the latter substance was without effect.
Elimination of Trimethoprim in Swine: Comparison of Results Obtained by Three Analytical Methods
Authors: Nielsen Poul , Rasmussen Folke
Published: July 2010

Abstract: 14C‐trimethoprim was administered to swine by intravenous injection. The concentration of trimethoprim in the plasma was determined by spectrophotometry, spectrofluorimetry and by liquid scintillation counting. There were only minor deviations between the spectrophotometric and the spectrofluori‐metric methods, as the metabolites which may interfere in the spectrophotometric analysis are formed only in very small amounts. More than 50 % of the administered dose was excreted in the urine within 5 hours. The total urinary excretion in 3 days was 75–80 % while only about 10 % was excreted in the faeces. Trimethoprim was extensively metabolized in swine. Less than 15 % of the dose was excreted unchanged in the urine.
Binding of Digitoxin to Human Serum Albumin: Influence of Ionic Strength and Ionic Medium on the Digitoxin‐Albumin Complex Formation
Authors: Brock Axel
Published: July 2010

Abstract: The binding of digitoxin to human serum albumin was studied under varying conditions with regard to the ionic strength and the ionic medium. At neutral pH and low ionic strength a substitution of Cl‐ by I‐ or SCN‐ was followed by an increased digitoxin‐albumin complex formation. The maximum binding affinity was obtained for Cl‐ > 0.4 mol/l, I‐ > 0.1 mol/l and SCN‐ > 0.05 mol/l. CCl3COO‐ was shown to be a powerful inhibitor of the digitoxin‐albumin interaction. At pH = 5 the binding affinity was uninfluenced by a substitution of Cl‐ by I‐ or SCN‐. Under similar conditions substantial variations of the ionic strength too, did not influence the binding affinity. The interpretation of this binding pattern was discussed with regard to a molecular mechanism for the digitoxin‐albumin interaction.
Collagen Profile in Rat Granulation Tissue after Cyclophosphamide Treatment
Authors: Hansen T. Mørk , Lorenzen I.
Published: July 2010

Abstract: The collagen profile was studied in 2–3 week old granulation tissue, induced in rats by subcutaneous implantation of viscose cellulose sponges. Cyclophosphamide was given daily intraperitoneally, in a dose of 10 mg per kg during the entire experiment, beginning either 7 days before or on the day of the sponge implantation. Cyclophosphamide caused an increase in the water percentage, and decreased the dry weight and the total amount of collagen in the granulomas, reflecting a suppression of collagen synthesis. The catabolism of collagen was also inhibited in the cyclophosphamide treated rats, as indicated by a fall in the content of free OH‐proline and a lowering of the alpha/beta ratio in acid extracted collagen. Cyclophosphamide treatment increased the collagen solubility in acetic acid and increased the aldehyde content in relation to OH‐proline in purified collagen. This indicates that cyclophosphamide may inhibit the cross‐linking of collagen by blocking the aldehydes or decrease the stability of the collagen molecule by decreasing the hydroxylation of proline. Pretreatment with cyclophosphamide did not influence the effect of cyclophosphamide given during the development of granulation tissue.
2,6‐cis‐Diphenylhexamethylcyclotetrasiloxane: Physico‐Chemical Properties and Analytical Methods
Authors: Spielvogel D. E. , Hanneman L. F.
Published: July 2010

Abstract: The characterization of 2,6‐cis‐diphenylhexamethylcyclotetrasiloxane is presented in two parts. The first part‐physico‐chemical data—includes melting point, boiling point, vapor pressure and solubility data as well as spectroscopic data from infrared, ultraviolet, nuclear magnetic resonance and mass spectroscopic experiments. The second section describes analytical chemistry methodology for quality control: gas chromatographic separation and quantitation and nuclear magnetic resonance spectroscopy measurements.
Methaemoglobin Reduction and NADH‐Dependent Methaemoglobin Reductase Activity Following DNBP‐ and Nitrite Induced Methaemoglobinemia in Sheep
Authors: Frøslie Arne
Published: July 2010

Abstract Haemoglobin, methaemoglobin, and NADH‐methaemoglobin reductase were investigated in sheep blood after intraruminal administration of DNBP and sodium nitrite at doses of 45 and 75 mg/kg b. wt., respectively. The sheep suffered from methaemoglobinemia at maximum levels of 5.5–7.5 g MetHb/100 ml blood after about 3 hours. The nitrite‐induced methaemoglobinemias were normalized during the first 12 hours, while the DNBP‐induced methaemoglobinemias lasted for 2–3 days or more. DNBP also caused serious haemolyses in the sheep after 1–2 days, and two of these animals died. The normal level of methaemoglobin reductase in 10 sheep was 3.3 ± 0.31 units. Nitrite had only a moderate and temporary effect on the reductase enzyme activity, while DNBP had a progressive and almost complete inhibitory effect on the enzyme.
Action of Mild Alkali on UDPGlucuronosyltransferase of Hepatic Microsomes
Authors: Marniemi Jukka , Vainio Harri
Published: July 2010

Abstract UDPGlucuronosyltransferase of rat liver microsomes was found to be activated by mild alkali treatment in vitro. Treatment with 0.4 M ammonia for 1 hr increased the specific activity of the enzyme more than three‐fold over the control level. On prolonged treatment, the activation was highest at lower concentrations; 0.02 M ammonia causes about three fold activation after 16 hrs treatment. About half of the measurable protein was solubilized from the micromes into the 105,000 × g supernatant after treatment with 0.4 or 0.2 M ammonia for 1 hr. More prolonged ammonia treatment was not equally effective in solubilizing microsomal protein. Mild alkali treatment increased the amount of biuret sensitive bonds from the microsomal membrane (about 20 % over the control level). Treatment at alkaline pH solubilized maximally only about 14 % of the measurable UDPglucuronosyltransferase into the 105,000 × g supernatant.
Chelation in Metal Intoxication. III. Lowering of Nickel Content in Poisoned Rat Organs
Authors: Tandon S. K. , Mathur A. K.
Published: July 2010

Abstract Six metal binding agents were screened in vivo for their ability to mobilise nickel from the brain, heart, kidney and liver of nickel poisoned rats. Out of these, 1,2 cyclohexylene dinitrilotetraacetic acid (CDTA) was most effective in removing the metal from the heart (78 %) followed by brain (76 %), kidney (65 %) and liver (57 %) whereas diethyl‐dithiocarbamate (DDC) was more effective in the order of heart (85 %), liver (51 %), kidney (44 %) and brain (32 %). Under in vitro conditions, CDTA, diethylene triaminepenta‐acetic acid (DTPA) and nitrilotriacetic acid (NTA) were found to be more effective in dialysing out nickel from the subcellular fractions of liver and kidney and the blood corpuscles of rats prctreated with nickel sulphate. In general, no correlation between the chemical structure or molecular weight of the chelators and their ability to remove nickel from the biological system was observed.
The Biliary Excretion of 3H–MannitoI and 3H–Ibuterol in Unanaesthetized Rats
Authors: Ryrfeldt Ake , Eriksson Hans , Hellström Wera , Johansson Maiken
Published: July 2010

Abstract The biliary clearances of 3H–mannitol (5 and 50 μmol/kg) and 3H–ibuterol (diisobutyrate ester of terbutaline) (0.5 and 5 μmol/kg) after intraarterial administration have been studied using unanaesthetized rats with uninterrupted enterohepatic circulation. The mean bile flow was 0.08 ml/min./kg. The biliary clearance of mannitol ranged from 0.06–0.17 ml/min./kg. The biliary clearance of ibuterol and its metabolites (total radioactivity) ranged from 2.05 to 4.81 ml/min./kg and that of the formed terbutaline from 0.53 to 2.05 ml/min./kg indicating a concentrative transfer from the plasma to the bile. The cumulative biliary excretion during the 3 hour sampling period amounted to 1 % of the administered doses of mannitol and 25 % of the doses of ibuterol.
Distribution and Elimination of 2–MethyI–4–Chlorophenoxyacetic Acid (MCPA) in Male Rats
Authors: Elo Heikki
Published: July 2010

Abstract The distribution and elimination of 2–methyl–4–chlorophenoxyacetic acid (MCPA) in male rats were studied. 3 mg of 14C–labelled and non–labelled MCPA in 50 % ethanol was injected into the stomach of male rats and urine, faeces and internal organs or tissues were analyzed for radioactivity. During the first 24 hrs 92.26 ± 5.36 % of the radioactivity was excreted in the urine and 6.76 ± 3.56 % in the faeces. Recovery in the urine and faeces after five days was 102.78 ± 1.10 % of the dose administered, indicating that practically all MCPA is eliminated in the urine and faeces. The maximum concentrations of MCPA in the tissues occurred between 2 to 8 hrs after administration. Thereafter the concentrations declined rapidly. The highest concentrations of MCPA were observed in the blood, kidney, lung, heart, suprarenal gland, liver, thyroid gland and bone marrow. The lowest concentrations were those in the brain, adipose tissue, testis and muscle.
Biochemical Changes and Pulmonary Response of Guinea Pigs to Asbestos Dust
Authors: Singh Jaswant , Beg M. U. , Kaw J. L. , Viswanathan P. N. , Zaidi S. H.
Published: July 2010

Abstract The biochemical and histopathological changes in lungs of guinea pigs were studied 120 days after intratracheal injection of three varieties of asbestos dusts, viz. chrysotile, amosite and anthophyllite. The salient histopathological features observed were the development of dust cell lesions in the lungs of animals exposed to the different varieties of asbestos. Maximum fibrosis and minimal asbestos body formation was observed in animals exposed to chrysotile and anthophyllite, respectively. With amosite and anthophyllite the development of diffuse interstitial fibrosis ensued, accompanied by well developed asbestos body formation in the amosite exposed animals. Biochemical studies revealed significant alterations in various phosphorylated compounds, an accumulation of orthophosphate and depletion of esters and nucleotides being very marked. RNA content increased significantly in the amosite treated group while the nucleic acid content remained unaltered in the chrysotile group.
Reduced Inactivation of Tyrosine Aminotransferase in the Perfused Rat Liver in the Presence of Ethanol
Authors: Mørland Jørg
Published: July 2010

Abstract Livers from fasted male rats (250–300 g body weight) were isolated and perfused. The effect of ethanol in the perfusate (approximate concentration 0.2 (w/v)) on the activity of tyrosine aminotransferase was investigated in the presence and absence of dexamethasone (final concentration 20 (μ/ml) and/or cycloheximide (final concentration 25 μg/ml). The following observations were made: (1) Ethanol increased tyrosine aminotransferase activity both in the presence and absence of dexamethasone. (2) The addition of ethanol or its main metabolite acetaldehyde to the enzyme assay mixture did not increase enzyme activity. Neither did ethanol reduce the leakage of enzyme from liver to perfusate or bile. (3) Tyrosine aminotransferase activity declined more slowly in ethanol‐treated livers than in control livers when protein synthesis was inhibited by cycloheximide. (4) Ethanol did not influence either the activity of another liver enzyme, tryptophan oxygenase, or the radioactivity remaining in labelled proteins 1 hr 30 min. after administration of cycloheximide. It is concluded that ethanol increased tyrosine aminotransferase activity in perfused livers by specific inhibition of enzyme inactivation.
The Pharmacology of a New Hypoglycaemic Agent N‐[4‐(2‐(2,3‐dihydrobenzo (b) furan‐7‐carboxamido)‐ethyl)‐ benzenesulphonyl]‐N′‐cyclohexylurea (NOVO CS 476). II. Pharmacological Studies on the Mechanism of Action
Authors: Jørgensen Karin Damm
Published: July 2010

Abstract The new sulphonylurea CS 476 does not potentiate the effect of insulin on plasma glucose levels in diabetic dogs in which an oral glucose load does not cause insulin release. In normal dogs propranolol 0.3 mg/kg intravenously inhibites the insulin release and the hypoglycaemia due to CS 476 suggesting involvement of β‐adrenergic receptors in its action on the pancreas. Pretreatment of dogs with phentolamine leads to an augmentation of the insulin response to CS 476.
The Pharmacology of a New Hypoglycaemic Agent N‐[4‐(2‐(2,3‐dihydrobenzo(b)furan‐7‐carboxamid o)‐ethyl) ‐benzenesulphonyl]‐N′‐cyclohexylurea (NOVO CS 476). III. General Pharmacological Studies
Authors: Jørgensen Karin Damm
Published: July 2010

Abstract The new sulphonylurea CS 476 was tested for positive inotropic effect on the isolated cat papillary muscle. Unlike tolbutamide CS 476 had no positive inotropic effect. CS 476 had no adverse effect on blood pressure in dogs, cats and rats nor on the electrocardiogram of dogs in doses up to ten times the therapeutic dose. Unlike chlorpropamide CS 476 did not potentiate the effect of exogenous antidiuretic hormone in hydrated dogs. In therapeutic concentrations the drug had no effect on smooth muscle preparations. 1,000–10,000 times therapeutic concentrations had a papaverine‐like effect ‐ similar to therapeutic concentrations of tolbutamide.
Secretion of Human Growth Hormone and Insulin in Levodopa Test during Carbamazepine Therapy
Authors: Syvälahti E. , Pynnönen S.
Published: July 2010

Abstract The effect of oral administration of carbamazepine for a period of three weeks on serum growth hormone, serum immunoreactive insulin, and blood glucose was studied in healthy volunteers using a levodopa stimulation test. Serum growth hormone rose significantly from 1.3 ± 0.3 ng/ml to 16.3 ± 3.4 ng/ml in 60 minutes after levodopa administration (1000 mg orally) before carbamazepine, and almost similarly from 2.3 ± 0.5 ng/ml to 15.1 ± 4.0 ng/ml after carbamazepine during the test. No consistent changes were found in blood glucose concentrations in the levodopa test before or after carbamazepine. Levels of serum IRI were also normal throughout the test and no impairment in insulin secretion was seen during carbamazepine treatment. It is suggested that carbamazepine does not lead to an altered anterior pituitary function or to an impairment in insulin secretion. This is of advantage when growing children or subjects with a risk factor for diabetes are treated.
Actions of Fenfluramine on Glucose Uptake in Vitro and in Vivo
Authors: Jórgcnsen Karin Damm
Published: July 2010

Abstract Fenfluramine stimulates the glucose uptake of the isolated hemi‐diaphragm from normal and streptozotocin diabetic rats in the presence of insulin. The drug does not cause an increased storage of glycogen. During hind leg perfusion of the dog fenfluramine stimulated peripheral glucose uptake. No increase in lactate or in free fatty acids release was observed during prolonged infusions of the drug. Fenfluramine caused an improvement of glucose tolerance in normal glucose‐primed rats. A single dose of fenfluramine significantly lowered the blood glucose levels in streptozotocin diabetic rats and in diabetic dogs treated with insulin. Prolonged treatment with fenfluramine of streptozotocin diabetic rats had no significant effect on blood glucose levels. Additional treatment for one week of insulin dependent diabetic dogs with small non‐anorexic doses of fenfluramine resulted in slightly decreased blood glucose levels. The dogs could not be maintained on fenfluramine alone (without insulin).
Antidiuretic and Urinary Cyclic AMP Response of Vasopressin in Normal Rats and in Rats with Lithium‐polyuria
Authors: Christensen Sten , Geisler Arne
Published: July 2010

Abstract The antidiuretic and urinary cyclic AMP response to supramaximal vasopressin infusion was studied in normal rats and in rats with lithium‐polyuria. The animals were anaesthetized and then infused with a solution designed to produce excessive water diuresis and to lower basal cyclic AMP excretion. In 6 control animals not infused with vasopressin (I) urinary cyclic AMP excretion decreased during the infusion period. Vasopressin infusion (300 μU/min.) con‐sistantly induced antidiuresis in all of 13 control rats (II); but the urinary cyclic AMP response varied individually from a significant increase in 6 animals to either no change or to a decrease in the remaining animals. The antidiuretic response to vasopressin was inhibited by 85 % in 10 animals with marked polyuria induced by lithium administration (III). None of the animals in this group showed a significant increase of cyclic AMP excretion in response to vasopressin. The average rate of cyclic AMP excretion, which was equal in the two groups before vasopressin, was signifimantly lower in group III than in group II during vasopressin infusion. It is suggested that the increase in cyclic AMP excretion during vasopressin antidiuresis, although not consistant, most likely reflects hormone‐induced changes of intracellular cyclic AMP levels in the renal medulla. Thus, the data suggest that the nephrogenic diabetes insipidus syndrome produced by lithium is associated with a defect in the renal formation of cyclic AMP in reponse to vasopressin.
Effect of Time on the Response to Cyanide Anoxia of Frog Heart Damaged by Isoproterenoi*)
Authors: Carlsten A. , Poupa O.
Published: July 2010

Abstract Isoproterenol (IPR) induces damage to the heart of frogs living at 25°. The resistance of an isometric ventricular strip to histotoxic anoxia induced by cyanide is significantly reduced 4 hours after one injection of IPR and still more after repeated injections. Macroscopically visible heart lesions are observed only on the first two days after the second injection of IPR. The response of the heart muscle preparation to cyanide is then continuously improved during 3‐4 weeks after IPR and the disturbance of the myocardial function is thus only temporary and may at least partly be induced by metabolites of the catecholamine.
Disposition of the Hypoglycaemic Sulphonylurea CS 476
Authors: Taylor T. , Gotfredsen C. , Chasseaud L. F. , Elsom L. F. , Franklin E. R.
Published: July 2010

Abstract The disposition of radioactivity was studied after administration of a new oral hypoglycaemic agent, 14C‐labelled CS 476, to rats, rabbits and dogs at a pharmacologically active dose level of 0.2 mg/kg and to human subjects at a therapeutic dose level of 5 mg. After oral doses, most of the drug was excreted in the faeces by rats and dogs and faecal radioactivity was obtained from biliary excretion. Rabbits and humans excreted most of the dose in urine. Unchanged CS 476 was the major radioactive component in the plasma of all the species during 6 hours after dosing, and was extensively bound to the plasma proteins. The half‐life of CS 476 in plasma was 2 hours in dogs and humans, and 16 hours in rabbits. Drug accumulation did not occur in dog and rabbit plasma during a period of consecutive daily doses and the half‐lives after the last of the repeated doses were similar to those found after single doses. In rats, plasma concentrations were relatively low, and did not reach the peak level found in female rats until 24 hours after dosing. CS 476 was extensively bio‐transformed. The apparent species‐dependent disposition of CS 476 may explain differences in tolerance to chronic doses.
Actions of Neurotensin and (Gln4)‐Neurotensin on Isolated Tissues
Authors: Rökaeus A. , Burcher E. , Chang D. , Folkers K. , Rosell S.
Published: July 2010

Abstract The actions of neurotensin and (Gln4)‐neurotensin have been investigated on a number of isolated tissues. They were ineffective in contracting the guinea pig vas deferens, the rabbit aortic strip or the frog rectus abdominis muscle in concentrations up to 0.24 γM. Neurotensin and (Gln4)‐neurotensin relaxed the rat duodenum at fairly high concentrations (24 nM). The guinea pig ileum contracted in response to increasing doses, although the maximum response were only one half that caused by histamine. Tachyphylaxis was observed at dose intervals of less than 12 minutes, but this tachyphylaxis did not inhibit responses to acetylcholine, histamine, 5‐HT or to DMPP, suggesting that the neurotensins may act at specific receptor sites. They contracted the rat fundus strip at concentrations of 0.24 nM and higher. The neurotensins and 5‐HT were approximately equipotent on this tissue, although the maximum respones was about 80 % of that to 5‐HT. The contractions of the rat fundus strip could not be blocked by atropine, hexamethonium, methysergide, morphine or by 7‐OH‐THC. These data indicate that neurotensin and (Gln4)‐neurotensin are equipotent as far as smooth muscle stimulating activity is concerned. Of those organs tested, the rat fundus strip seems to be the most suitable one for studies concerning structure‐activity relationships.
Kinetics of the Binding of Salicylazosulfapyridine to Human Serum Albumin
Authors: Jansen Jens Aas
Published: July 2010

Abstract In order to elucidate the possibility of the dissociation rate of drugs from plasma proteins presenting a rate limiting step in the elimination of drugs by secretion (renal or biliary) and metabolism, the kinetics of salicylazosulfa‐pyridine (SASP) binding to human serum albumin (HSA) has been investigated by stopped‐flow photometry. Equilibrium dialysis showed that HSA has three classes of binding sites for SASP with 0.93, 2.3 and 8.4 sites, respectively, and association constants of 2.1 · 106, 1.4 · 105 and 3.0 · 103 M‐1, respectively. The association rate constants for the first and second classes are 4.4 · 106 and 1.5 · 107 M‐1 sec.‐1, and the dissociation rate constants are 2.1 and 109 sec.‐1. At SASP concentrations resulting from the usual therapeutic doses about 83 % will bind to the first class binding sites. The dissociation “half time” for this class being 0.34 sec., leads to the conclusion that dissociation rates of this order of magnitude are unlikely to reduce the rate of metabolism or biliary secretion whereas it may reduce renal tubular secretion. Whether this is the case depends on the intrinsic rate constant of secretion.
Rapid Gas Chromatographic Assay of Serum Diazepam, N‐Desmethyldiazepam, and N‐Desalkylflurazepam
Authors: Linnoila Markku , Dorrity Floyd
Published: July 2010

Abstract A rapid procedure for the measurement of serum diazepam (D), N‐desmethyldiazepam (ND), and N‐desalkylflurazepam (NF), levels in clinical samples is described. The single step extraction procedure yields quantitative extraction for the drugs mentioned above. No solvent evaporation step is needed. No interference of endogenous substances or generally used psychotropic drugs containing halogen atoms has been observed. The conditions provide excellent precision, due to a clear separation of the internal standard, medazepam, from the solvent front. The frequency response electron capture detector provides a linear response to the drugs over a 5 × 102 concentration range making serial dilution of the samples unnecessary. The automatic data reduction system indicates the serum levels directly in ng/ml without manual calculations.
Effect of a Selective 5‐HT Uptake Inhibitor — Lu 10–171 *— on Rat Brain 5‐HT Turnover
Authors: Hyttel John
Published: July 2010

Abstract: Changes in endogenous concentrations of 5‐HT and 5‐HIAA as well as the turnover rate of 5‐HT was studied in rat brain after treatment with a new potent and selective inhibitor of the neuronal 5‐HT reuptake mechanism, Lu 10–171 (1‐(3‐(dimethylamino)propyl)‐1‐(p‐fluorophenyl)‐5‐phthalancarbonitrile). After a single dose of Lu 10–171 the concentration of 5‐HIAA was reduced from 1 to 24 hours after treatment, whereas that of 5‐HT was practically unchanged, indicating decreased turnover of 5‐HT in the brain. This was confirmed using three different methods for measuring 5‐HT turnover. Thus the rate of 5‐HIAA accumulation in the brain after probenecid was reduced after Lu 10–171. Likewise treatment with Lu 10–171 led to a decreased fall in 5‐HT and an increased fall in 5‐HIAA after inhibition of 5‐HT synthesis with parachloro‐phenylalanine (PCPA). Unexpectedly Lu 10–171 did not change either the accumulation of 5‐HT or the decrease in 5‐HIAA after inhibition of MAO with pargyline. By and large the results are consistent with the proposed negative feed‐back regulation of 5‐HT neuronal firing rate due to the abundance of 5‐HT at postsynaptic receptors after inhibition of the reuptake mechanism.
Antidiuretic and Urinary Cyclic AMP Response of Vasopressin in Normal Rats and in Rats with Lithium‐polyuria
Authors: Christensen Sten , Geisler Arne
Published: July 2010

Abstract: The antidiuretic and urinary cyclic AMP response to supramaximal vasopressin infusion was studied in normal rats and in rats with lithium‐polyuria. The animals were anaesthetized and then infused with a solution designed to produce excessive water diuresis and to lower basal cyclic AMP excretion. In 6 control animals not infused with vasopressin (I) urinary cyclic AMP excretion decreased during the infusion period. Vasopressin infusion (300 μU/min.) consistantly induced antidiuresis in all of 13 control rats (II); but the urinary cyclic AMP response varied individually from a significant increase in 6 animals to either no change or to a decrease in the remaining animals. The antidiuretic response to vasopressin was inhibited by 85% in 10 animals with marked polyuria induced by lithium administration (III). None of the animals in this group showed a significant increase of cyclic AMP excretion in response to vasopressin. The average rate of cyclic AMP excretion, which was equal in the two groups before vasopressin, was signifimantly lower in group III than in group II during vasopressin infusion. It is suggested that the increase in cyclic AMP excretion during vasopressin antidiuresis, although not consistant, most likely reflects hormone‐induced changes of intracellular cyclic AMP levels in the renal medulla. Thus, the data suggest that the nephrogenic diabetes insipidus syndrome produced by lithium is associated with a defect in the renal formation of cyclic AMP in reponse to vasopressin.
Pharmacology of cis (Z) ‐ Clopenthixol Decanoate, a Depot Neuroleptic
Authors: Pedersen V. , Svendsen O. , Danneskiold‐Samsøe P. , Boeck V. , Nielsen. I. Møller
Published: July 2010

Abstract: The duration and intensity of the neuroleptic effect of cis(Z)‐clopenthixol decanoate in Viscoleo$rG have been compared with those of cis(Z)‐clopenthixol, 2 HCl in aqueous solution in a number of animal experimental models. Cis(Z)‐clopenthixol, 2 HCl had a strong, but short‐lasting neuroleptic effect (apomorphine antagonistic effect in dogs, inhibition of conditioned avoidance response in rats) which was accompanied by marked sedation. In contrast, cis(Z)‐clopenthixol decanoate in oil had an effect which was slower in onset, but of much longer duration and only the highest doses caused a slight sedation. In rats catalepsy could be induced in some animals by high doses of cis(Z)‐clopenthixol decanoate whereas cis(Z)‐clopenthixol, 2 HCl at all the doses tested caused catalepsy in all animals. In mice only high doses of cis(Z)‐clopenthixol decanoate in oil caused reduction of spontaneous motor activity and potentiation of barbiturate anaesthesia. The results are discussed with special reference to the clinical use of the depot preparation.
Chronic Copper Poisoning in Sheep. III. The Distribution of Soluble Copper‐ and Zinc‐binding Liver Proteins of Lambs compared with Adult Sheep
Authors: Søli Nils E. , Frøslie Arne , Norheim Gunnar
Published: July 2010

Abstract: The distribution of copper and zinc among soluble hepatic proteins in lambs from 1 normal and 1 copper dosed ewe was studied by gel filtration. It was found that the distribution pattern is similar in newborn lambs and their dams. The amount of copper in the liver indicated that a placental transfer and accumulation of copper is possible in lambs.
Hexachlorobenzene Induction of 2,4‐Diaminoanisole Mutagenicity in Vitro
Authors: Dybing Erik , Aune Tore
Published: July 2010

Abstract: Hexachlorobenzene (HCB)‐pretreatment of rats leads to an increase in liver microsomal 2,4‐diaminoanisole activation to a mutagen after a dose of 10 mg/kg intraperitoneally and to an increase in ethylmorphine N‐demethylase after a dose of 50 mg/kg intraperitoneally. 2,4‐Diaminoanisole mutagenicity was increased 24 hrs after HCB‐pretreatment, whereas ethylmorphine N‐demethylase first increased after 48 hrs. There is a sex difference in the inducing effects of HCB on ethylmorphine N‐demethylase, but not on 2,4‐diaminoanisole mutagenicity. HCB‐pretreatment also leads to increases in 2,4‐diaminoansiole mutagenicity in the kidneys, but not in the lungs or in foetal liver.
Bioavailability of Oxazepam: Absence of Influence of Food Intake
Authors: Melander A. , Danielson K. , Vessman J. , Wåhlin E.
Published: July 2010

Abstract: The possible influence of food intake on the bioavailability of the anxiolytic drug oxazepam was assessed in eight healthy volunteers taking a single dose of the drug both on an empty stomach and together with a standardized breakfast meal. The serum concentrations of oxazepam were determined by gas chromatography on samples obtained before, and at numerous occasions up to 48 hours after drug administration. The results indicate that concomitant food intake has no essential influence on the bioavailability of oxazepam.
The Composition and Distribution of PCB in Arctic Fox (Alopex lagopus) Caught near Longyearbyen on Svalbard
Authors: Norheim Gunnar
Published: July 2010

Abstract Samples from 44 arctic foxes (Alopex lagopus), caught near Longyearbyen on Svalbard, were analyzed with respect to their content of PCB. Gas chromatographic‐mass spectrometric investigations revealed that 7 PCB components constituted the main part of the total PCB present. These components were quantified individually. A moderate degree of PCB contamination was recorded. Calculated on a fat weight basis, the total concentrations of PCB in fat tissue and liver were about equal, but the relative amounts of most of the PCB components present were different in the 2 tissues. The total amount of PCB in brain, calculated on a fat weight basis, was significantly less than the corresponding concentrations in liver, kidney, muscle, and fat tissue. The special distribution trend observed in this study is related to the structure of the PCB components present and the arctic nature of the sampling area.
Inhibition by Neuroleptics of Uptake of 3H‐GABA into Rat Brain Synaptosomes
Authors: Fjalland B.
Published: July 2010

Abstract Neuroleptics from various chemical groups and some amino acids were examined for GABA uptake‐inhibiting properties in rat brain synaptosomes. The phenothiazine and thioxanthene neuroleptics inhibited GABA uptake by 50% in the concentration range of 10–30 μM. No difference in potency was found between the cis and the trans isomers of the thioxanthenes. Clozapine and particularly sulpiride were weak inhibitors of the GABA uptake process, whereas some of the butyrophenones examined exhibited rather potent effect. Specific GABA uptake inhibitors (nipecotic acid and guvacine) were as active as the most potent butyrophenones. As no significant correlation was obtained between GABA uptake‐inhibiting effect of the neuroleptics and their clinical or pharmacological effects it is concluded that the influence on GABA uptake is not an important aspect of the neuroleptic action.
Mammary Tumour Inhibition and Subacute Toxicity in Rats of Prednimustine and of Its Molecular Components Chlorambucil and Prednisolone
Authors: Fredholm B. , Gunnarsson K. , Jensen G. , Müntzing J.
Published: July 2010

Abstract Prednimustine, a chlorambucil ester of prednisolone, retarded growth of DMBA‐induced mammary tumours in rats and reduced the number of tumours. A combination of chlorambucil and prednisolone (C + P) in the same proportion as in prednimustine, had similar effects, 8 and 16 mg per kg of the C + P combination being equipotent to 16 and 64 mg per kg of prednimustine, respectively. The mortality figures suggested that prednimustine was considerably less toxic than equipotent doses of C + P. This toxicity difference was confirmed in a parallel investigation of the subacute toxicity in rats of prednimustine and C + P. This study showed that the mortality, reduction of lymphocytes and platelets, and bone marrow depression was much lower after prednimustine than after equimolar amounts of the C + P combination. The results suggest that the low toxicity of prednimustine makes this drug a better cytostatic agent than the C + P combination treatment.
On the Disulfiram‐Like Effect of Coprine, the Pharmacologically Active Principle of Coprinus atramentarius
Authors: Carlsson A. , Henning M. , Lindberg P. , Martinson P. , Trolin G. , Waldeck B. , Wickberg B.
Published: July 2010

Abstract Coprine or disulfiram was given to rats in various doses at various time intervals before the administration of 2 g/kg ethanol. The ratio acetaldehyde/ethanol in the alveolar air was measured by gas chromatography and was taken as an index of the aldehyde dehydrogenase (ALDH) activity. The activity of dopamine β‐hydroxylase (DBH) was estimated in the same animals by measuring the amount of 14C‐octopamine formed from 14C‐tyramine in the heart. Coprine and disulfiram both caused an increase in the acetylaldehyde/ethanol ratio, coprine being more potent than disulfiram. Disulfiram, but not coprine, reduced the net yield of 14C‐octopamine. In rats pretreated with either coprine or disulfiram, blood‐pressure and heart‐rate were recorded before and after intraperitoneal injections of 0.4 g/kg ethanol. In both cases ethanol caused a marked and rapid fall in blood‐pressure. However, this effect was accompanied by tachycardia only in animals treated with coprine. It is concluded that coprine like disulfiram inhibits ALDH, but only disulfiram causes an additional inhibition of DBH. This difference may account for differences in the cardiovascular response to ethanol
Formation of Asbestos Bodies under the Influence of Parenteral Iron Overload
Authors: Narang S. , Kaw J. L. , Zaidi S. H.
Published: July 2010

Abstract The effect of parenteral administration of iron (dextran) on the number of asbestos fibers in the lungs, formation of asbestos bodies and the development of interstitial fibrosis was studied in guinea pigs exposed intratracheally to anthophyllite dust. The treatment did not accelerate, either qualitatively or quantitatively, the formation of asbestos bodies or retard the development of interstitial fibrosis. The number of naked asbestos fibers was also similar in anthophyllite‐inoculated animals to those similarly inoculated, but having had, additionally, a previous saturation with iron.