bluuebunny/crossref_metadata_2025 huggingface dataset:
Reaction of Cationic Groups of Chlorpromazine with Anionic Macromolecules: Complexes with DNA, RNA, Hyaluronic Acid and Heparin
Authors: Blumenkrantz N. , Asboe‐Hansen G.
Published: July 2010

Abstract: In vitro, chlorpromazine forms complexes with DNA, RNA, hyaluronic acid and heparin. Irradiation with ultraviolet light induces chemical degradation of chlorpromazine. These phenomena are discussed in relation to chlorpromazine‐induced lupoid syndrome with antinuclear factors in the blood serum of human patients as well as to photo‐toxic and photo‐allergic dermatoses.
Catabolism of Orally Administered l4C‐Histamine in Man
Authors: Sjaastad Ottar , Sjaastad Ö. V.
Published: July 2010

Abstract: In previously published studies only 33–66% of the radioactivity was recovered in the urine after oral administration of 14C‐histamine. In the present study the corresponding figures were higher: between 68 and 80% of the administered 14C‐activity was recovered in the urine within the first 48 hours of administration. Between 1.8 and 18% was exhaled as 14CO2, whereas between 13 and 19% of the administered radioactivity was excreted in the faeces. Thus nearly 100% of the administered 14C‐activity was recovered. Urinary 14C‐metabolites of histamine were determined by isotope dilution technique and by autoradiography. We were unable to obtain a constant specific activity for 1.4‐methylimidazole‐acetic acid by isotope dilution technique and an estimate of the balance between the urinary metabolites could not be obtained by this technique. Autoradiography indicated that oxidative deamination is the main pathway of orally administered histamine, and that imidazoleacetic acid riboside is the main urinary metabolite.
Competition between p‐Aminophenol, p‐Nitrophenol, and Bilirubin for Glucuronidation in Cultures of Rat Hepatoma Cells and Homogenates of the same Cells
Authors: Rugstad Hans Erik , Dybing Erik
Published: July 2010

Abstract: Glucuronidation of p‐aminophenol (PAP), p‐nitrophenol (PNP), and bilirubin has been studied in cultures of a clonal cell line with liver‐like functions and homogenates from the same cells. The purpose was to study the effect of simultaneous addition of substrates to cultures of living cells and to homogenates with an excess of UDPGA, and to compare the glucuronidation rates in living cells and in homogenates from the same cells, fortified with UDPGA. The rates of glucuronidation of PAP, PNP, and bilirubin by cells in culture were about 50, 70, and 15 nmol/mg protein/hour respectively. In fortified cell homogenates the respective glucuronidation rates were about 500, 1800, and 15 nmol/mg protein/hour. PNP inhibited the glucuronidation of PAP and bilirubin both in cell cultures and cell homogenates. PAP inhibited the glucuronidation of bilirubin in cell cultures. Bilirubin did not inhibit the glucuronidation of the other substrates. PNP glucuronide did not inhibit the glucuronidation of bilirubin or PAP in cell cultures or homogenates.
Inhibition of the Antigen‐induced Release of Histamine from Guinea‐pig Lung by Terbutaline
Authors: Sörenby Lars
Published: July 2010

Abstract:The inhibitory effect of terbutaline and isoprenaline on the anaphylactic release of spasmogens from the lung tissue of the ovalbumin‐sensitized guinea‐pig was investigated. In the tested concentrations 2 × 10‐9‐2 × 10‐5M terbutaline showed a dose‐dependent inhibition in all except the lowest concentration. Isoprenaline was about twenty times as potent as terbutaline in preventing the release of histamine.
Effects of the Herbicide 2,4,5‐Trichlorophenoxyacetic Acid on Growth and Morphology of L 929 Cells
Authors: Dragsnes L. , Helgeland K. , Jonsen J.
Published: July 2010

Abstract: A dose‐dependent inhibition of growth was found when monolayer cultures of L 929 cells were grown in the presence of 2,4,5‐trichlorophenoxyacetic acid (2,4,5‐T) in concentrations from 0.25 to 2.25 mM. At 1.75 and 2.25 mM an almost immediate cessation of growth was found. On removal of the herbicide (2.25 mM) after incubation for 3 or 6 days, cell multiplication was resumed after a lag period of about 24 hours. In the presence of 0.5 to 2.25 mM 2,4,5‐T an accumulation of particles in the cytoplasm was observed, and on prolonged incubation in the presence of 2.25 mM 2,4,5‐T the cells became rounded and detached from the substratum. By replacing the test medium by the control medium, however, the particles in the cytoplasm disappeared and the cells resumed their fibroblast‐like structure.
Hepatic Porphyrin Synthesis in Rats After Pretreatment with Polychlorinated Biphenyls (PCBs)
Authors: Grote Wynand , Schmoldt Achim , Benthe Hans F.
Published: July 2010

Abstract: A single dose of polychlorinated biphenyls caused an increase of δ‐aminolevulinic acid synthetase activity and porphyrin content in rat liver. δ‐aminolevulinic acid dehydratase activity was not altered significantly. A maximum effect was obtained 24 hrs after treatment, and the rate limiting enzyme of porphyrin synthesis returned to a normal level of activity at the third day after treatment. On the contrary the porphyrin content of the liver remained elevated up to 4 weeks after a single injection of polychlorinated biphenyls. After administration of polychlorinated biphenyls the kinetic properties of δ‐aminolevulinic acid synthetase of rat liver were found to be altered: an increase of Vmax was accompanied by a decrease of Km. The threshold dose for an increase of δ‐aminolevulinic acid synthetase activity and porphyrin content of rat liver after a single dose of polychlorinated biphenyls was about 0.019 mmol/kg body weight for starved animals. At this dose range no significant differences in response of the parameters examined were seen when polychlorinated biphenyls with variable chlorine contents were administrated. A maximum effect for δ‐aminolevulinic acid synthetase was obtained by a threefold dose, and no further increase was obtained by much higher doses, whereas increasing response up to these high doses was seen for the porphyrin content of the liver. At high doses the activity of δ‐aminolevulinic acid synthetase increased with increasing chlorine content of the polychlorinated biphenyls.
The Effect of Chlorhexidine on some Enzyme Activities of Rat Liver Lysosomes and Peroxisomes
Authors: Jensen Jam Erik , Bleeg Henry , Christensen Flemming
Published: July 2010

Abstract: The effect of chlorhexidine (Chx) on some enzyme activities of rat liver lysosomes and peroxisomes was studied. A concentration dependent stimulation of lysosomal acid phosphatase was observed, the stimulation being maximal above 300 μM Chx. The acid phosphatase activity was released to an extent of 50% by Chx as compared to a release of nearly 100% caused by Triton X‐100. The lysosomal β‐N‐acetylglucosaminidase activity was stimulated by Chx with a maximum at 50 μM Chx. At higher concentrations of Chx the activity declined and above 300 μM the activity reached the level of the control. The activity was not significantly solubilized by Chx as compared to about 90% solubilized by 0.1% Triton X‐100. The peroxisomal catalase activity was precipitated almost totally at 3000 x g by 1000 μM Chx and the catalase activity was 50% depressed at 100 μM Chx and 70% at 1000 μM Chx. Peroxisomal urate oxidase was stimulated slightly by Chx. The activity reached a constant level of 125% of the control above 100 μM Chx. No activity was released from the peroxisomes by Chx. The mode of action of Chx is discussed in the light of the present results.
Pharmacokinetics of Cyclophosphamide in Renal Failure
Authors: Mouridsen Henning T. , Jacobsen Erik
Published: July 2010

Abstract: The metabolism of cyclophosphamide was determined in five patients with severe renal insufficiency. After the intravenous injection of 14C‐cyclophosphamide the activities due to unchanged cyclophosphamide and metabolites were determined in samples from urine and serum for 2–3 days. Only 22% of the injected radioactivity could be recovered in the urine during the first 3 days as against the normal of some 65%. The rate of biotransformation seemed normal and in agreement with these findings a very long term retention of metabolites could be demonstrated. The clinical implications of these results are discussed.
Effects of Single Doses and Daily Administration of Pyrithioxine (pyritinolum, NFN, rINN) on the Alcohol Withdrawal Syndrome in Rats
Authors: Hillbom M. E. , Kosunen A.‐L. , Nikander P. , Pösö A. R.
Published: July 2010

Abstract: Male Wistar rats were made physically dependent on ethanol by intragastric administration (4‐‐10 g/kg/day) for 20 days. The dose of ethanol was adjusted to maintain the maximal level of intoxication compatible with adequate intake of a liquid diet. After withdrawal of ethanol a few animals developed spontaneous tonic‐clonic convulsions. A marked increase in susceptibility to sound‐induced convulsions and decrease in sensitivity to pain were observed in the rats after withdrawal, and their serum and red cell Mg++ contents were found to be significantly lower and red cell K+ content higher than in controls. Therapeutic amounts (0.01 g/kg/day) of pyrithioxine (pyritinolum NFN, rINN) (bis‐(3‐hydroxy‐4‐hydroxymethyl‐2‐methylpyridyl‐(5)‐methyl)‐disulphide dihydrochloride monohydrate) given with the ethanol for 20 days made the rats with withdrawal symptoms significantly more responsive to pain and slightly but insignificantly less susceptible to sound‐induced withdrawal convulsions, but this pretreatment did not markedly prevent the deviations in electrolyte concentrations. Large amounts of the drug (0.2‐‐0.3 g/kg/day), however, increased the number of spontaneous withdrawal convulsions. Acute administration of pyrithioxine (0.01 g/kg) after cessation of the intoxication period did not mitigate the withdrawal symptoms, and massive amounts (2 g/kg) killed the animals within a few hours. Voluntary alcohol consumption of Alko AA rats (a high‐consumer strain) was not altered by pyrithioxine. The results indicate that pyrithioxine may affect the symptoms of ethanol withdrawal in different ways, the effect depending on both dose level and time of administration. It is suggested that the reason for the slight beneficial effect of pyrithioxine on the withdrawal symptoms when taken regularly in combination with ethanol is the slight protection afforded against intoxication.
Parabolic Relationship between Lipophilicity and Biological Activity of Aliphatic Hydrocarbons, Ethers and Ketones after Intravenous Injections of Emulsion Formulations into Mice
Authors: Jeppsson Roland
Published: July 2010

Abstract: The relationship between lipophilicity and isoeffective doses of aliphatic hydrocarbons, ethers and ketones has been determined after intravenous injections into mice. Because of the low water solubility of these pharmacons they were injected by using a lipid emulsion formulation of low toxicity. The pharmacological parameters determined were: dose necessary for loss of righting reflex (“AD100”) and highest tolerated amounts (“LD100”) after continous infusion at a constant speed and acute toxicity in 50 % of the animals (LD50) after bolus injection. It was concluded that the relationship between lipophilic character (logP) and isoeffective dose (log 1/C) was satisfied by the general equation log 1/C = a (log P)2 + b (log P) + c for all three groups of pharmacons and thus followed a parabolic pattern.
Some Naturrally Occurring Skin Irritants
Authors: Evans F. J. , Kinghorn A. D. , Schmidt R. J.
Published: July 2010

Abstract: Thirteen esters were isolated from the fresh latex of four species of the genus Euphorbia. Structures were elucidated by infra‐red, nuclear magnetic resonance and mass‐spectroscopy, together with circular dichroism spectroscopy, of the esters and their derivatives or hydrolysis products. Eight of these compounds were new esters of 12‐deoxy‐phorbol. All the isolated esters produced inflammation of the skin and their relative potencies were assessed by the mice ear test for irritant effects. These compounds were of two types. The first group were diesters with an acetate moiety at carbon 20 and a long chain fatty acid at carbon 13; the second group were mono‐esters with a free C‐20 hydroxyl group. The mono‐esters were more potent than the diesters and their irritant effects were longer lasting. Within both groups of irritants an increase in the chain length of the C‐13 acid produced an increase in the irritation of the esters. It was also observed that unsaturation in the side chain increased the potency.
Distribution of Sodium, Potassium and Lithium in the Brain of Lithium‐treated Rats
Authors: Edelfors Sven
Published: July 2010

Abstract: The distribution of lithium, and the effect of lithium on sodium and potassium in various parts of the rat brain were investigated. For this purpose a technique was developed by which the rat brain could be dissected in reproducible anatomical brain parts. Lithium was distributed unequally in the various brain parts. The concentration in hemispheres, cerebellum, thalamus and grey matter from the hemispheres was at the serum level, i. e. about 0.5 meq./kg of fresh tissue. The concentration in the hypothalamus and in white matter from the hemispheres was about 1.0 meq./kg of fresh tissue. Treatment with lithium had no influence on the potassium content in the brain whereas the sodium concentration was lowered about ten per cent in the hypothalamus and in the white matter of the hemispheres.
Acute Sodium Fluoride Toxicity in Rats in Relation to Age and Sex
Authors: Mörnstad Håkan
Published: July 2010

Abstract: The 24 hour LD50 dose for intraperitoneally injected sodium fluoride was determined in developing and young adult rats of both sexes. The developing animals tolerated two and a half times as much fluoride as the young adults when expressed as mg FVkg of body weight. There were no significant differences between the two sexes. The 24 hour LD50 values were: 4 day old females 45 (39–52), males 40 (34–48); 20 day old females 47 (39–57), males 51 (47–55); 60 day old females 30 (21–43), males 28 (17–42); 90 day old females 21 (17–26), males 20 (17–24) mg F‐/kg of body weight.
Mass Fragmentographic Determination of 2,6‐cis‐Diphenylhexamethylcyclotetrasiloxane in Human Serum
Authors: Hammar Carl‐Gustaf , Freij Grethel , Strömberg Signhild , Vessman Jörgen
Published: July 2010

Abstract: The concentration of 2,6‐cis‐diphenylhexamethylcyclotetrasiloxane in the first patients given the drug has been determined by means of mass fragmentography. The fragment, m/e=405 (M‐15)+, was used together with the isotope masses 406, 407, and 408 to trace the compound in the heptane extracts of the serum samples. As internal standard served the trans isomer. The sensitivity of the method is 0.1 ng/ml serum.
Effects of Oral 2,6‐cis‐Diphenylhexamethyl‐cyclotetrasiloxane on the Reproductive System of the Male Macaca Mulatta
Authors: Vier R.R. Le , Bennett D.R. , Hunter M.J.
Published: July 2010

Abstract: An organosilicon compound, 2,6‐cis‐diphenylhexamethylcyclotetrasiloxane, cyclic 2,6‐cis‐[(PhMeSiO)2(Me2SiO)2], is a novel structure possessing estrogenic, antigonadotropic and antifertility activity in the rat. Cyclic 2,6‐cis‐[PhMeSiO)2 — (Me2SiO)2], was administered orally for 28 days to mature male rhesus monkeys to assess effects on the histology of the reproductive system and the tissue distribution of cyclosiloxane‐derived silicon. Other groups were given estradiol benzoate (0.05 mg/kg) subcutaneously for comparison. Both compounds stimulated various degrees of sexual skin edema; a known estrogen‐dependent response in the monkey. Picnotic nuclei appeared in the epithelium of the caput epididymis, at 0.1 mg/kg of the cyclosiloxane and gross tubular atrophy was evident at 10 mg/kg. Estradiol benzoate had little or no effect on these tissues. Disruption of spermatogenesis occurred at 1.0 mg/kg cyclosiloxane and above. The secretory activity of the prostate was suppressed at 10 mg/kg and above, and the epithelial cells of the seminal vesicles showed some signs of atrophy at 100 mg/kg, the highest dose tested. Estradiol benzoate suppressed the secretory activity of both sex accessory tissues. Cyclic 2,6‐cis‐[(PhMeSiO)2 (Me2SiO)2] enlarged the livers at all dose levels and decreased spleen weight at 100 mg/kg. Estradiol was without effect in this regard. The distribution of cyclosiloxane‐derived silicon was primarily to bile, fat, lymph nodes, urine, adrenals, testes, prostate, liver, pituitary, and epididymis in decreasing order of silicon concentration. The increase of silicon in the pituitary following treatment with cyclic 2,6‐cis‐[(PhMeSiO)2 (Me2SiO)2] is consistent with the proposed antigonadotropic mechanism. The data presented here have demonstrated that subacute oral dosing of the male rhesus monkey with cyclic 2,6‐cis‐[(PhMeSiO)2(Me2SiO)2] results in an antigonadotropic action generally comparable to the action of subcutaneously administered estradiol benzoate.
The Hormonal and Antifertility Activity of 2,6‐cis‐Diphenylhexamethylcyclotetrasiloxane in the Female Rat*
Authors: Le Vier R. R. , Jankowiak M. E.
Published: July 2010

Abstract: An organosilicon compound, 2,6‐cis‐diphenylhexamethylcyclotetrasiloxane, cyclic 2,6‐[(PhMeSiO)2(Me2SiO)2], was shown to be an orally active estrogen in the mature castrate rat; about 1.0 mg/kg is equivalent to 0.005 mg/kg estradiol benzoate used as a maximum stimulatory dose in a uterotropic assay. Cyclic 2,6‐cis‐[(PhMeSiO)2 (Me2SiO)2] is not an antiestrogen.

Cyclic 2,6‐cis‐[(PhMeSiO)2 (Me2SiO)2] is an effective oral postcoital antifertility agent when administered at 0.33 mg/kg on days 1–5 of gestation and at 3.0 mg/kg given on day 1 of gestation. The primary effect appeared to be accelerated passage of ova to the uterus and induction of ovum destruction in the oviduct. At the doses used cyclic 2,6‐cis‐[(PhMeSiO)2 (Me2SiO)2] was similar to diethylstilbestrol in that tubal retention did not occur as shown for estradiol benzoate. Administration of cyclic 2,6‐cis‐[(PhMeSiO)2 (Me2SiO)2] at other times during gestation terminated pregnancy during primitive streak and neurula stages (days 8–11). Gestation was less sensitive to organosiloxane treatment during implantation. Pregnancy was not terminated after day 11. Thus, this purely organosilicon compound represents a new class of moderate estrogens and may be useful in the study of estrogen structure‐activity relationships.
Renal Functions in Hens Fed Graded Dietary Levels of Ochratoxin A
Authors: Svendsen Carl , Skadhauge Erik
Published: July 2010

Abstract Renal functions: Glomerular filtration rate (inulin clearance), tubular excretion rate of PAH (p‐aminohippurate), and concentrating ability (osmotic urine to plasma ratio after injection of vasopressin) were measured in hydrated, conscious hens. The purpose of the investigation was to measure the effects of ochratoxin A, a nephrotoxic secondary metabolite of fungi. Four experimental groups were examined. A control group, two groups with exposure for 49 weeks to a low and a high level of contamination, and a third group exposed at the high level for 2 weeks. The average GFR was reduced by 12% in the first group, by 28% in the second, and by 8% in the third group. Similar reductions were found in the total plasma protein concentration by 14%, 17%, and 2% respectively. The renal concentrating ability in the three groups was reduced by approximately 15%. The tubular excretion of PAH was not reduced at low plasma concentrations, but reduced by 1/2 at higher concentrations. In control birds the excretion of PAH followed Michaelis‐Menten kinetics. The apparent “Km” was 53.2 mg/100 ml, the Tmax 20.4 mg/kg min. The ultrafiltrable fraction of plasma PAH was 0.86. The renal changes are in accordance with morphological changes reported elsewhere, and show that the levels of ochratoxin A used in this study are significantly nephrotoxic.
Methoxyethyl Mercury Toxicity in Pigs: Kidney Function and Mercury Distribution
Authors: Gyrd‐Hansen N. , Helleberg A.
Published: July 2010

Abstract Female pigs were fed methoxyethyl mercury‐contaminated feed at two levels: 11 and 44 mg Hg per kg feed, corresponding to a daily dose of 0.45 and 1.80 mg Hg per kg b.wt. The pigs on the lower dose level were exposed for 12 weeks without any obvious signs of toxicity, while the pigs on the higher dose level died after 8 weeks. The disease occurring during this intoxication resulted mainly from injury to the kidney, and the renal function tests demonstrated a pronounced fall in kidney function in the pigs on the high dose level. Accordingly, changes in renal structure were found in these pigs consisting of tubular degeneration and excessive connective tissue formation. Tissue analysis for mercury showed a distribution between the organs similar to that characteristic for inorganic mercury, indicating a rapid metabolism of methoxyethyl mercury. The renal excretion of mercury seemed to increase with time of exposure but never exceeded ten per cent of the inulin clearance.
Studies on the Uptake of 14C‐Neostigmine in Rat Diaphragm: Effects of Chronic Treatment with Anticholinesterases and Chronic Denervation
Authors: Christensen Chr. Broen , Helleberg Lars , Dallmer Jan
Published: July 2010

Abstract The uptake of 14C‐neostigmine in the isolated diaphragm was studied after chronic treatment of rats with either neostigmine or diisopropyl fluorophosphate (DFP) and following chronic denervation of the left hemidiaphragm. The uptake was measured as muscle‐to‐medium 14C‐concentration ratio after 3 hours incubation of hemidiaphragms with 3 × 10‐7M 14C‐neostigmine. Subcutaneous injections of neostigmine 150 μg per day for 7 days or DFP 165 μg per day for 10 days to rats weighing 190–220 g resulted in a highly significant increase of 14C‐neostigmine uptake in the isolated diaphragm. Chronic denervation did not affect the 14C‐neostigmine uptake. The results demonstrate that chronic administration of anticholinesterases induce changes in the diaphragm, which result in an increased uptake of 14C‐neostigmine in the isolated muscle.
The Effect of Lithium on Unstimulated and Glucagon‐stimulated Urinary Cyclic AMP Excretion in Rat and Man
Authors: Geisler A. , Vendsborg P. B. , Johannesen M. , Klysner R. , Thomsen J.
Published: July 2010

Abstract The purpose of this study was to determine whether lithium also inhibits hormone‐stimulated adenylate cyclase in vivo. The effect of long‐term lithium treatment on unstimulated and glucagon‐stimulated cyclic AMP excretion was studied in the rat and in man. The influence of lithium on plasma glucagon degradation was also investigated. It was found that in the rat lithium doubled unstimulated and glucagon‐stimulated urinary cyclic AMP excretion. In lithium treated rats plasma glucagon concentrations thirty minutes after intraperitoneal injection were twice that of the control rats. In man, lithium affected neither cyclic AMP excretion nor glucagon degradation. These results offer no support for the hypothesis that in vivo lithium in general inhibits hormone‐stimulated adenylate cyclase. However, in the intact organism lithium may have additional pharmacological actions, and complex regulatory mechanisms which may modify the cyclic AMP metabolism. Therefore it may be premature to conclude that lithium per se does not have an inhibitory action on glucagon‐sensitive adenylate cyclase in vivo.
The Pharmacokinetics of Cyclophosphamide in Man Following Treatment with Methotrexate
Authors: Mouridsen H. T. , Jacobsen E. , Faber O.
Published: July 2010

Abstract The metabolism of cyclophosphamide was determined before and following treatment with methotrexate. After 9 days treatment to 7 patients with methotrexate 7.5 mg/day by mouth the rate of bio‐transformation of cyclophosphamide was decreased in 2 cases, increased in 1 case and unchanged in 5 cases. After the intravenous injection of 40 mg methotrexate to 2 subjects the biotransformation of cyclophosphamide is immediately inhibited. It is argued that the inconsistency of the results after prolonged treatment with methotrexate may be due to individual variations with regard to sensitivity of the drug metabolizing enzymes to methotrexate, whereas the acute effect is probably due to an inhibition of the action of the enzymes.
Change in Plasma Renin Substrate in Lithium–intoxicated Nephrectomized Rats, and the Effect of Sodium on Plasma Renin and Plasma Renin Substrate in Lithium–intoxicated Rats
Authors: Kierkegaard–Hansen Alex
Published: July 2010

Abstract The possible effect of lithium intoxication on the synthesis of renin substrate was investigated in rats given food containing 70 mmol of lithium and 125 mmol of sodium/kg dry weight for nine days. The increase in renin substrate five hours after bilateral nephrectomy was found to be identical with the increase in control rats given no lithium. This indicates that the decrease in renin substrate seen during lithium intoxication is solely a result of the increased concentration of plasma renin. A second experiment examined whether administration of extra sodium might counteract the changes in plasma renin substrate and plasma renin that occur during lithium intoxication. In lithium–treated rats given a low–sodium diet there was a pronounced fall in renin substrate and a rise in renin as compared to the control rats. These changes were almost abolished by the administration of a high–sodium diet, but this also led to a fall in the serum lithium concentration. After administration of additional lithium, the change in renin substrate was the same as in the lithium–treated low–sodium group, and the change in renin was intermediate. The data indicate that sodium counteracts the changes in plasma renin substrate and plasma renin by increasing the renal lithium clearance, but that in addition the change in plasma renin which occurs during lithium intoxication, may be counteracted by sodium through other mechanisms.
Genetic Variation of Drug–Metabolizing Enzymes in the Wistar Rat
Authors: Marselos Marios
Published: July 2010

Abstract Rats of the Wistar/Af/Han/Mol/(Han 67) strain were preselected for the inducibility of the hepatic soluble aldehyde dehydrogenase, after treatment with phenobarbital (80 mg/kg daily, intraperitoneally, for 4 days) and open liver biopsy. Animals with highly induced aldehyde dehydrogenase also had a 50 and 40 % difference in the induction of D–glucuronolactone dehydrogenase and NADPH–cytochrome c reductase respectively. Other enzymes of the hepatic drug hydrox–ylation and glucuronidation did not show significant variation in the induction pattern between the two genetic groups. After inbreeding, the second filial generation was used in order to determine enzyme activities without any pretreatment. The basal activities of aldehyde and D–glucuronolactone dehydrogenase, but not of NADPH–cytochrome c reductase, were also different in the untreated animals. Urinary excretion of D–glucaric acid was the same in the two groups, both in the basal and the induced state.
Separation of Kininogens by Gel Filtration of Plasminogen–free Human Plasma
Authors: Briseid Kjell , Korbu Astri , Johannesen Siri
Published: July 2010

Abstract High molecular weight kininogen (S1) is useful as a sensitive substrate in assays of the kininogenase activity of plasma kallikrein, but considerable difficulties are encountered in the isolation of this kininogen due to loss by “spontaneous” activation. In the present work a satisfactory yield (40–60 %) of a crude preparation of S1 was obtained through gel chromatography on Sephadex G–200 of plasminogen–free 60°‐heated human citrated plasma. Low molecular weight kininogen (S2) was also obtained by the same procedure. The two kininogen preparations did not contain significant amounts of inhibitors of human plasma kallikrein, hog pancreas kallikrein or human plasmin, as judged by the stability of the arginyl–esterase activities of these enzymes in contact with the kininogens. Both S1 and S2 were stable for at least one year when stored at ‐20°. A preparation of human plasma kallikrein reacted specifically with S1, while both hog pancreas kallikrein and human plasmin also reacted with S2. The quantitative data are in accordance with the assumption that hog pancreas kallikrein and plasmin release bradykinin from S1 and kallidin from S2. The rate of release of kinin produced by hog pancreas kallikrein in S2 occurred twice as fast as in S1, while the opposite was registered for plasmin.
High Uptake in the Erythrocytes and the Spleen of the Quaternary Dipyridylium Salt Paraquat Injected Intravenously in Hypotonic Solutions
Authors: Oskarsson Agneta , Tjälve Hans
Published: July 2010

Abstract Intravenous injections of the quaternary dipyridylium salt paraquat (14C–labelled) dissolved in solutions of low tonicity result in a high uptake in the erythrocytes and concomitantly also in the spleen (red pulp), the latter being probably due to phagocytosis of paraquat–containing erythrocytes by the reticuloendothelial system. Higher tonicities of the injected solutions result in a low uptake and the same applies to oral, intraperitoneal and subcutaneous injections. Paraquat was present in the erythrocytes in a non–metabolized form without being bound to membranes or proteins. The uptake in the erythrocytes was not influenced by alterations of the pH or by the preparation of a charge–transfer complex with serotonin in the injection solutions. Chemical alterations of the paraquat in the injection solutions could not be detected. In vitro the uptake of paraquat in the erythrocytes was higher in the haemolysed (and then reconstituted by adding sodium chloride) erythrocyte–ghosts than in the non–haemolysed erythrocytes, as shown by incubations at various tonicities. It is proposed that the intravenous injections of paraquat in hypotonic solutions temporarily alter the membranes of the erythrocytes in the blood–stream and make them permeable to paraquat, possibly, as judged from the in vitro experiments, only during a short period of partial haemolysis. The distribution studies also showed a retention of paraquat in the lungs. In addition paraquat was accumulated in the melanin of the tissues.
The Influence of Lithium on Water Binding Ability, Consistency and Macromolecules in the Rat Brain
Authors: Edelfors Sven
Published: July 2010

Abstract Wistar male rats were treated with lithium for 50, 80, and 120 days, respectively. Lithium was added to the diet (40 mmol/kg of diet), the plasma lithium concentration being in the range of 0.55–0.70 mmol/l of plasma. The treatment caused a significantly more rigid consistency of the brain tissue. The water content and water binding ability in various parts of the brain ‐ measured by a drying course ‐ was unchanged. The content of hexosamine and protein in total brains was significantly decreased (about 10 per cent) after the treatment. The content of chondroitin sulphate in various parts of the brain was unchanged, whereas the content of hyaluronic acid was significantly increased in the cerebellum (25 per cent) and in the thalamic area (20 per cent). The results suggest an influence of lithium on the macromolecules from the extracellular space, causing an alteration of the neuronal function.
Unchanged Protein Binding and the Increase of Serum Diazepam Levels after Food Intake
Authors: Korttila K. , Kangas L.
Published: July 2010

Abstract Seven subjects received diazepam 0.3 mg/kg intravenously twice with a 2‐week interval between the doses. The subjects ingested a fatty or carbohydrate meal in a cross‐over fashion 4 hours after the injection on both experimental days. Venous blood samples were drawn 2, 3, 4, 5 and 6 hours after the injection of diazepam for measurement of the serum levels of total and free (unbound) diazepam, N‐desmethyldiazepam, and free fatty acids. Serum levels of diazepam decreased progressively with time until the food intake, after which a significant (P < 0.01) postprandial increase (average 23 %) occurred with both diets as compared to the preprandial levels at 4 hours (average 240 ng/ml). Serum levels of free fatty acids decreased significantly both after a fatty (P < 0.01) and a carbohydrate (P < 0.05) meal. Diazepam was extensively (96 to 98 %) bound to proteins and no changes in its protein binding was found. It is concluded that the late impairment of psychomotor skills that occurs with an increase in the diazepam serum level after its intravenous administration is due rather to its re‐mobilization from a storage site than to variations in its protein binding.
Effect of Fluoride on Glycerol Production in Rat Adipocytes in Vitro
Authors: Holland Roy I.
Published: July 2010

Abstract The effect of 10 mM fluoride on glycerol production in vitro from rat epididymal adipocytes was investigated. Fluoride had no effect on the basal glycerol production, irrespective of the presence or absence of Ca++ and Mg++ ions. When stimulating the glycerol production with 10 mM theophylline, fluoride reduced the stimulation in the absence of either Ca++ or Mg++ or both. In the presence of both ions, fluoride had no effect on the theophylline stimulation. Fluoride also reduced the stimulative effect of adrenaline on glycerol production, but not that of glucagon. Increased adrenaline concentration could not overcome the inhibitory effect of fluoride.
Pharmacokinetic Studies on Clopenthixol Decanoate; A Comparison with Clopenthixol in Dogs and Rats
Authors: Aaes‐Jørgensen T. , Overø K. Fredricson , Bøgesø K. P. , Jørgensen A.
Published: July 2010

Abstract The release from the depot, hydrolysis and distribution in the organism as well as the metabolism and elimination of intramuscularly injected Clopenthixol decanoate in Viscoleo® have been studied in dogs and rats with radioactive as well as non‐labelled drug after single as well as repeated administration. The studies clearly demonstrate the depot effect of Clopenthixol decanoate given intramuscularly in oil compared to orally administered clopenthixol. The amounts of drug remaining at the site of injection in dogs suggest monoexponential release of drug from the depot and a half‐life of 4‐5 days. Rapid hydrolysis to Clopenthixol in the organism was indicated by in vitro experiments and in vivo findings. Clopenthixol was found to be the main compound in the organism after single as well as repeated doses. The Clopenthixol formed by hydrolysis appeared to be metabolized in the same way as clopenthixol given orally i. e. by dealkylation of the side chain and by S‐oxide and N‐oxide formation. The elimination pattern with predominant fecal excretion also appeared to be the same after Clopenthixol and its esterified derivative apart from the reflection in the latter case of the slow release from depot. A rapid exchange in the organism between tritium from the drugs and hydrogen from the body water was demonstrated. This has to be considered in studies with tritium labelled drugs, where estimation of total radioactivity gives the sum of tritium in drug, metabolites and water.
Selectivity of Food Colours for Different Organic Acid Transport Systems in Rat Renal Cortex
Authors: Carlson John
Published: July 2010

Abstract Seventeen food colours were tested as inhibitors of the simultaneous uptake of labelled o‐iodohippurate and iodipamide into slices of rat renal cortex. The results have been interpreted in terms of inhibition of two different anion‐transport systems: the hippurate or H‐system and the liver‐like L‐system. No clearcut relation was found between inhibition ability and system specificity on the one hand and molecular weight or structure on the other. However, most disulphonic azo dyes and quinoline yellow show an L‐system affinity while tri‐ and tetra‐sulphonic azo dyes, triarylmethanes and erytrosine show very little predilection for either of the two systems.
Reversibility of the Effects of Cyclophosphamide on Collagen: Biochemical Studies on Skin and Granulation Tissue and Determination of Thermal Stability of Tail Tendons of Rats
Authors: Hansen T. Mørk , Andreassen T. T. , Lorenzen I.
Published: July 2010

Abstract Granulation tissue was produced in rats by subcutaneous implantation of viscose cellulose sponges. Treatment with cyclophosphamide in a dose of 10 mg/kg/day for 14 days caused an increase in acid soluble OH‐proline and a decrease in alpha/beta ratio of acid soluble collagen of granulation tissue. Forty‐two days of continuous cyclophosphamide treatment caused a decrease in dry weight, in free OH‐proline, and in salt soluble OH‐proline in granulation tissue. These findings are in accordance with previous observations of a decreased collagen synthesis and an inhibited collagen degradation in granulation tissue after cyclophosphamide treatment. In skin, the only change after cyclophosphamide was a decrease in total content of OH‐proline and an increase in alpha/beta ratio of acid soluble collagen after 42 days of treatment. No effect of the subcutaneous sponge implantation was observed on the collagen variables in the skin. In comparison with unstarved controls, a reduction in dry weight and in free OH‐proline in granulation tissue, as well as an increase in salt soluble OH‐proline in the skin were observed 28 days after a 14‐day treatment with cyclophosphamide. These observations indicate a sustained effect of cyclophosphamide on collagen 28 days after cessation of treatment. In addition the thermal stability of rat tail tendons was decreased 28 days after withdrawal of cyclophosphamide to the same extent as after starvation for 42 days and after 42 days of continuous cyclophosphamide treatment. It is concluded that the cyclophosphamide‐induced collagen alterations, which may be of importance in the anti‐inñammatory action of cyclophosphamide, are only in part reversible, 28 days after cessation of 14 days of cyclophosphamide treatment.
The Effect of Nitrazepam on Manual Skill, Grip Strength, and Reaction Time with Special Reference to Subjective Evaluation of Effects on Sleep
Authors: Lahtinen Ulla , Lahtinen Antti , Pekkola Pentti
Published: July 2010

Abstract The effects of 5 and 10 mg oral nitrazepam doses on manual skills, grip strength, and reaction time 8 hours after ingestion of the drugs were studied in 34 healthy female volunteers aged 19–22 years. 5 mg nitrazepam caused a slight but insignificant decrease in psychomotor skills. With 10 mg psychomotor skills were influenced significantly. Grip strength and reaction time were not influenced either by the 5 or 10 mg doses. The investigators corroborate the value of the established effects of nitrazepam as a hypnotic, but recommend that caution should be exercised in prescribing the drug as a hypnotic (especially in doses exceeding 5 mg) to work‐aged subjects as there is a risk of significant effect on the psychomotor skills. Furthermore, the drug may cause fatigue.
Time Course of the Effect of Insulin on Bovine Mesenteric Artery
Authors: Arnqvist Hans J.
Published: July 2010

Abstract The time course for the effect of insulin on the bovine mesenteric artery, a medium sized artery with a high content of smooth muscle, was studied. The arteries were preincubated for varying times (0–180 min.) with and without insulin. The magnitude of the insulin effect, subsequently assayed on the accumulation of glucose carbon and the distribution of 3–0‐methylglucose, was found to increase with the time of prior exposure to insulin, approaching a maximum after about 120 min. Insulin exposure also augmented its effect on the incorporation of leucine‐14C into protein in a similar way. Preincubation without insulin had no appreciable influence on the magnitude of the insulin effect, indicating that the sensitivity to the hormone did not change with time. The threshold concentration for the effect of insulin on glucose‐14C accumulation was 0.01 U/ml without preincubation and 0.001 U/ml after prior exposure to the hormone for 180 min. An action on protein syntheis may be involved in the increase in the magnitude of the insulin effect caused by prior exposure to insulin since no increase was found after inhibition of protein synthesis by puromycin.
Glucose and Cation Transport in Rat Jejunum, Ileum and Colon in vivo: Effects of Anionic and Nonionic Surfactants, and of Desoxycholate
Authors: Sund Reidar Bredo , Matheson Ingrid
Published: July 2010

Abstract Osmotically balanced solutions of glucose (0.5–300 mM) and sodium chloride, containing surfactants, were instilled into the small or large intestine of anaesthetized rats. Net absorption or secretion of glucose, sodium and potassium was studied. The surfactants tested were dodecylsulphate (3.4–17 mM), dioctyl‐sulphosuccinate (1.8–11 m/M), Lubrol WX (0.1–0.5%), Triton × 100 (0.25%) and desoxycholate (2.5 mM). Qualitatively, the results were similar to those obtained previously with cationic compounds, suggesting a common mode of action for all surfactants studied. 17 mM dodecylsulphate seemed to abolish completely physiological glucose transport in the jejunum and ileum. At a lower concentration, and with the other surfactants, normal glucose transport was affected to an intermediate extent.
Organochlorine Compounds in Norwegian Human Fat and Milk
Authors: Brevik E. M. , Bjerk J. E.
Published: July 2010

Abstract Analyses were carried out in 1975/76 of 58 samples of human, perirenal fatty tissue and 45 samples of human milk with regard to persistent organochlorine compounds. A corresponding investigation was carried out in 1969/70. A comparison of the results suggests that a decrease in the content of DDT and its metabolites occurs. The PCB content showed a significant increase as compared with 1969/70. HCB levels of approx. 0.25 ppm and 0.0054 ppm were demonstrated in fatty tissue and in human milk, respectively. Concentrations of DDT plus metabolites, PCB and HCB in older people were significantly higher than those found in younger subjects.
Effect of Colchicine on Drug Absorption from the Rat Small Intestine in Situ and in Vitro
Authors: Venho V.M.K. , Koivuniemi A.
Published: July 2010

Abstract The effect of colchicine (1 mg/kg intraperitoneally on two successive days) on the absorption of isoniazid, quinidine and sulphafurazole (sulfisoxazole) from the rat small intestine was studied in situ and in vitro. Colchicine produced two different types of histological damage in the small intestine, one with degenerative and the other with regenerative changes predominating. The small intestinal surface area was variably reduced. The colchicine‐treated rats were lethargic and hypothermic as compared to controls. Colchicine retarded the disappearance of fluid and all three drugs from the small intestinal lumen in situ 2 days after the first colchicine injection. In vitro the total amounts of fluid and drugs passed through the intestinal wall were not significantly changed by colchicine, although there was a slight tendency towards an increased absorption of quinidine. Hence, colchicine as an antimitotic drug decreases drug absorption from the rat small intestine in situ, apparently due to the decreased surface area of the small intestine, the decreased water flux through the intestinal wall, the retarded intestinal motility and hypothermia of the rats. In vitro the changes are small, which makes the in vitro tests less suitable for studying the effect of colchicine on absorption.
The Binding of CTAB, a Cationic Surfactant, to the Rat Erythrocyte Membrane
Authors: Isomaa Boris , Bergman Henrik , Sandberg Per
Published: July 2010

Abstract The adsorption of CTAB (cetyltrimethylammonium bromide) to the rat erythrocyte membrane was studied by determining the electrophoretic mobility of erythrocytes treated with CTAB and by SDS polyacrylamide electrophoresis of membrane proteins from erythrocytes treated with 14C‐CTAB. At low concentrations of CTAB there was only a small reduction in the electrophoretic mobility of the erythrocytes. At lytic concentrations the electrophoretic mobility of the erythrocytes was markedly reduced. Alterations at the cell surface were found to be a more likely reason for the reduction in the electrophoretic mobility than interactions between the surfactant and charged groups at the cell surface. Very small amounts of radioactivity were found to be associated with the protein and sialoglycoprotein bands of the polyacrylamide gels. It is suggested that the adsorption of CTAB to the rat erythrocyte membrane does not involve electrostatic interactions between the surfactant and negatively charged groups of the sialoglycoproteins and that membrane proteins do not play a major role in the lytic events.
Effect of Oral Administration of Calcium Carbonate, Carnalox® and Novaluco® on Plasma Gastrin Concentration in Duodenal Ulcer Patients
Authors: Nilsson Göran , Hjelmquist Ulf , Brodin Ernst
Published: July 2010

Abstract In 6 patients having duodenal ulcer disease plasma gastrin concentrations were determined before and after the oral administration of 0.5‐2 g of calcium carbonate, 2‐4 tablets of Carnalox® and 2 tablets of Novalucol®. No significant influence on basal plasma gastrin levels was noted indicating that antacids, whether they contain calcium carbonate or not, do not influence the basal plasma concentration of gastrin at occasional administration.
Methotrexate Concentrations in Biological Fluids: Comparison of Results Obtained by Radioimmunoassay and Direct Ligand Binding Radioassay
Authors: Virtanen Raimo , Iisalo Esko , Parvinen Martti , Nordman Eeva
Published: July 2010

Abstract A sensitive (sensitivity 2.2 × 10‐9 mol/1) and specific (practically no cross‐reaction with circulating folates) radioimmunoassay for the determination of methotrexate concentrations in biological fluids is described and compared with a commercial competitive protein binding assay. Antiserum with high titer was produced in rabbits immunized with MTX‐human serum albumin conjugate. Fitness for use in pharmacokinetic drug level determinations was shown in three patients, who received both low doses and high dose therapy combined with citrovorum factor rescue. An excellent correlation was found between plasma and urine MTX concentrations obtained by RIA and competitive protein binding assay. A two‐compartment pharmacokinetic model was found adequately describing the serum decay curves, but there was a great interindividual variability in the calculated pharmacokinetic parameters.
Pharmacokinetics of Nitrazepam in Saliva and Serum after a Single Oral Dose
Authors: Kangas L. , Allonen H. , Lammintausta R. , Salonen M. , Pekkarinen A.
Published: July 2010

Abstract The pharmacokinetics of nitrazepam in saliva and serum was studied in 12 healthy volunteers after a single administration of a 5 mg nitrazepam tablet. The binding of nitrazepam to plasma proteins was determined 4 hours after the administration by ultracentrifugation. The analysis of nitrazepam concentrations was performed by 63Ni‐EC‐GLC. The pharmacokinetic parameters were evaluated manually or by AUTOAN‐program in serum, and manually in saliva. The concentrations of nitrazepam in serum and saliva correlated significantly (r=0.472, P<0.001, n=97). The ratio saliva: serum was, however, time dependent. The protein free fraction in serum was significantly higher (P<0.01) than the salivary concentration at the same time (4 hours after administration). The peak concentrations in serum and saliva were 40.7 and 1.9 ng/ml (P<0.001) and the times to reach the peak maximum 2.4 and 2.5 hours, respectively (difference not significant). The mean half‐life of nitrazepam in serum was 30.5 hrs and in saliva 39.9 hrs, the difference being significant at P<0.05. The distribution phase parameters, poorly described before, were calculated. The clinical value of nitrazepam analysis in saliva seems to be negligible.
Effects of Adrenergic P‐Blockers and a Membrane Stabilizing Agent on Ouabain‐Induced Cardiac Arrhythmias in Anaesthetized Guinea Pigs
Authors: Åberg G. , Adler G. , Duker G. , Ek B. , Telemo E.
Published: July 2010

Abstract The antiarrhythmic effects of dl‐propranolol, d‐propranolol, metoprolol and lidocaine against ouabain‐induced cardiac arrhythmias were studied. It was found that contrary to earlier findings in the dog, the effects of the adrenergic β‐blockers against ouabain‐arrhythmias in guinea pigs were due to β‐blocking activity and not the membrane‐stabilizing activity of the compounds. The cardioselective β‐blocker, metoprolol, was more or equally effective as dl‐propranolol against ouabain‐induced arrhythmias in guinea pigs.