bluuebunny/crossref_metadata_2025 huggingface dataset:
Distribution and Fate of the Insect Repellent 14C‐N,N‐diethyl‐m–toluamide in the Animal Body. I. Distribution and Excretion after Injection into Mice
Authors: Blomquist Lars , Ströman Lars , Thorsell Walborg
Published: July 2010

Abstract: The tissue distribution of 14C‐labelled N,N‐diethyl‐m‐toluamide (DEET), a widely used mosquito repellent, was studied in mice basically by means of whole‐body autoradiography. After intravenous injection of the substance high tissue concentrations of radioactivity were found mainly in the liver, kidney, lacrimal gland, and nasal mucosa. At short time intervals after injection concentrations above the blood level were also seen in the thyroid and brown fat. Quantitative measurements revealed that the highest uptake was present in the lacrimal gland where radioactivity was also retained longer than in other tissues. Rapid excretion of the substance was found to take place mainly through the kidney. Thus, by 4 hours after injection, very little radioactivity remained in all tissues except the lacrimal gland. A placental barrier for the substance was observed, with much lower concentration in the foetuses of pregnant mice than in the mother.
The Inhibition of the Mitochondrial NADH Oxidase by Alprenolol and the Protective Effect of Cytochrome P‐450
Authors: Grundin Robert , Thor Hjördis , Orrenius Sten
Published: July 2010

Abstract: The presence of the β‐receptor blocking drug alprenolol at a low concentration was found to inhibit markedly the uptake of oxygen catalyzed by liver or heart mitochondria in the presence of β‐hydroxybutyrate but not in the presence of succinate. The same was true for the endogenous oxygen uptake by heart slices but not by liver slices or isolated liver cells. In the latter two systems, the rate of oxygen uptake was inhibited only at considerably higher concentrations of the drug. However, in the presence of SKF 525‐A — which prevents the binding of alprenolol to cytochrome P‐450 — liver slices and isolated liver cells were as sensitive as isolated mitochondria to the inhibitory effect on oxygen uptake by alprenolol. Furthermore, liver homogenates or combinations of the liver mitochondrial and microsomal fractions, in the presence or absence of NADPH, exhibited almost the same sensitivity towards the inhibitory effect of alprenolol on oxygen consumption as the mitochondrial fraction. Thus, the results indicate that alprenolol is a rather potent inhibitor of NADH‐linked mitochondrial oxidations, its site of action being localized between NADH and ubiquinone. In the intact liver cell, however, the mitochondria seem to be largely protected from this toxic effect by trapping of the drug by cytochrome P‐450. This may in turn be of importance for decreasing the hepatic toxicity of the high concentrations of alprenolol resulting from the efficient liver extraction after oral administration of this drug.
Distribution of 14C‐Morphine and Macromolecules in the Brain and Liver and their Nuclei in Pregnant Rats and their Foetuses after Infusion of Morphine into Pregnant Rats at Near‐Term
Authors: Steele William J. , Jóhannesson Torkell
Published: July 2010

Abstract: Timed‐pregnant (day 21 or 22) Sprague‐Dawley rats were administered 14C‐morphine (2.85 mci/mmol) 5 mg/kg/hr, or saline in equivalent volumes, by continuous intravenous infusion for periods of up to 4 hrs. The brains and livers of the maternal rats and of their foetuses were collected and their nuclei were isolated. The tissues and nuclei isolated from them were analyzed for DNA, RNA, protein content and radioactivity. Morphine infused maternal rats exhibited no significant difference in the total amounts of DNA, RNA and protein in the brain or in the concentration of these constituents in brain nuclei. Foetuses of morphine infused mothers exhibited no significant difference in the total amounts of macromolecules in the brain or in the concentration of DNA and protein in brain nuclei. It was found, however, that the concentration of nuclear RNA in foetal brain of morphine infused mothers was significantly lower at 4 hrs than that of saline infused controls. It was concluded that RNA synthesis in foetal brain must be much more sensitive to the inhibitory effect of morphine on macromolecular synthesis than that in maternal brain. The change in nuclear RNA concentration in foetal brain became significantly different when morphine reached its highest level in foetal brain nuclei. The morphine concentration (pmol 14C‐morphine equivalents per mg DNA) in the brain of foetal and maternal rats was the same at each time period, whereas the maternal liver levels were at least eight times greater than those in foetal liver. The concentrations in foetal brain nuclei were 2–14 times greater than those in maternal brain nuclei, whereas levels in the latter were found to be low and virtually constant at all time periods tested. Similar differences were found between foetal and maternal liver nuclei when the results were expressed as a percentage of the concentration in respective liver tissue. It was concluded that foetal brain nuclei have a greater capacity to bind or retain morphine than maternal brain nuclei and the phenomenon of differential distribution of morphine within brain cells is, among other factors, related to differences in sensitivity to morphine analgesia and other effects of morphine in young and old rats. The results were interpreted in terms of an inhibitory effect of morphine on transcription in foetal brain resulting from intranuclear accumulation of morphine.
The Effect of Dodecylsulphate upon Net Sodium and Water Transport from Tied Jejunal Loops in Anaesthetized Rats
Authors: Sund Reidar Bredo
Published: July 2010

Abstract: Into tied jejunal loops in rats solutions of sodium chloride or sulphate were instilled, with or without addition of sodium dodecylsulphate. The sodium salt concentration was varied, so that there was either a sodium concentration gradient from the plasma to the lumen, or a gradient from the lumen to the plasma. In the presence of surfactant, net secretion took place when there was a significant gradient from the plasma to the lumen, and net absorption when the gradient was reversed. With only a small gradient from the lumen to the plasma there was complete inhibition of net sodium transport. In principle, sodium in the presence of dodecylsulphate was transported along its concentration gradient. In control experiments, sodium absorption essentially independent of sodium concentration occurred. The results indicate that with dodecylsulphate, normal carrier‐mediated net sodium absorption is successively substituted by passive diffusion, as the surfactant dose‐dependently causes increased epithelial permeability to sodium. Less than 1.7 mM dodecylsulphate seemed to cause this effect.
Dibenzepine and its Metabolites in Blood, Muscle, Liver, Vitreous Body and Urine from Fatal Poisoning
Authors: Christensen Hanne , Felby Søren
Published: July 2010

Abstract: This paper presents a separation technique followed by spectrophotometry for the quantitative determination of dibenzepine and its main metabolites in autopsy material. The method, which has a lower detection limit of 0.5 μg/g material, was used for blood, tissue and urine from 8 cases in which dibenzepine was considered to be the only or a contributory cause of death. In addition to unchanged dibenzepine, three N‐demethylated metabolites were detected and identified in the material. According to the results the material could be divided into two groups. One group, six cases, with high concentrations of total dibenzepine (dibenzepine plus metabolites), blood 23–147 μg/g, liver 255–566 μg/g, in which death was caused by dibenzepine alone or in combination with alcohol, and another group, two cases, with ten times lower total dibenzepine concentrations in blood and tissue; in this group additional factors might have contributed to death.
The Crystal and Molecular Structure of 2,6‐cis‐Diphenylhexamethylcyclotetrasiloxane*
Authors: Carlström D. , Falkenberg G.
Published: July 2010

Abstract: The crystal structure of 2,6‐cis‐diphenylhexamethylcyclotetrasiloxane, C18H28O4Si4, has been determined and refined using three‐dimensional X‐ray diffractometer data. The unit cell is monoclinic, space group C2/c with the constants a=15.155, b=8.829, c=18.020 Å, β=93.44°. There is half a formula unit in the asymmetric unit. The structure was solved by direct methods and refined by least‐squares procedures. The final R‐value was 0.048 for 2144 symmetry independent observed reflexions.

The eight‐membered siloxane ring has a “boat form” and differs thereby from configurations earlier reported for cyclotetrasiloxanes. The intra‐ and intermolecular distances are discussed.
Quantitative determination of metoprolol in plasma and urine by gas chromatography
Authors: Ervik Magnar
Published: July 2010

Abstract: A procedure for the gas chromatographic determination of the β‐receptor blocking agent metoprolol at therapeutic levels in plasma and urine is described. Metoprolol is made electron capture sensitive by a derivatization reaction with trifluoroacetic anhydride. The method permits determination of concentrations of metoprolol down to about 5 ng/g of sample with a standard deviation of 0.7 ng. Automation of the gas chromatographic procedure gives a capacity of 24 samples a day.
Distribution of some Protein‐bound Trace Elements among Soluble Protein Fractions from Human Liver
Authors: Norheim Gunnar , Steinnes Eiliv
Published: July 2010

Abstract The soluble proteins from two samples of normal human liver were subjected to gel filtration. Zinc, cadmium, mercury, copper, arsenic, and selenium were determined in each molecular weight fraction by neutron activation analysis. The results are presented as “protein‐trace element spectra”.
Acute and Chronic Effects of Vasopressin in Rats with Lithium‐polyuria
Authors: Christensen Sten
Published: July 2010

Abstract The acute and chronic effects of vasopressin were studied in rats with polyuria due to long‐term administration of lithium. In anaesthetized, water‐loaded animals, lithium pretreatment producing severe polyuria inhibited the response to physiological doses of arginine vasopressin by 95 % as compared with the response in non‐treated rats with polydipsia induced by glucose drinking. The per cent inhibition of vasopressin response was somewhat reduced by increasing the dose of the hormone. There was no difference in osmolality of renal medullary tissue from lithium‐polyuric and glucose‐polydipsic rats when determined at the end of the experiments. Daily subcutaneous injections of 7.5 U/kg vasopressin (pitressin tannate oil suspension) to conscious animals, kept in metabolic cages, caused a significant antidiuretic response in rats with severe lithium‐polyuria (i.e. urine flow >50% of body weight daily and Uosm<200 mosmol/kg) and almost completely reversed the urine flow in animals with partial concentration defect. The results are compatible with the view that lithium‐polyuria in rats is due to impairment of the renal response to vasopressin. Being virtually unresponsive to physiological doses of vasopressin, however, the polyuria can be partly reversed by increasing the level of circulating hormone.
Disulfiram as a Tool in the Studies on the Metabolism of Acetaldehyde in Rats
Authors: Tottmar O. , Marchner H.
Published: July 2010

AbstractThe liver acetaldehyde dehydrogenases and the acetaldehyde level in the blood during ethanol metabolism were studied in rats 24 hrs after the administration of disulfiram. High doses of disulfiram (150–600 mg/kg) caused a threefold decrease in the activity of the mitochondrial low‐Kmenzyme, whereas no significant effects were found on the activity of the high‐Kmenzymes present in the mitochondrial, the microsomal and the cytosolic fractions. The concentration of acetaldehyde was threefold higher in the hepatic venous blood and fivefold higher in the peripheral blood in rats given disulfiram compared to rats given ethanol only. Low doses of disulfiram (25–50 mg/kg) decreased the activity of the low‐Kmenzyme by 26 %, and caused a significant increase in the liver output of acetaldehyde. The rate of ethanol elimination decreased by 35 % at a high dose of disulfiram, whereas the alcohol dehydrogenase activity was not influenced. It is suggested that the mitochondrial low‐Kmenzyme has a primary role in the regulation of the hepatic output of acetaldehyde, and the results will be discussed with special reference to the site and kinetics of acetaldehyde oxidation during ethanol metabolism in rat liver.
The Influence of Crimidin Metabolized by Liver on Brain Glutamic Acid Decarboxylase in Vitro
Authors: Hansen Kate L.
Published: July 2010

Abstract Liver homogenized in phosphate buffer was incubated with different amounts of crimidin for 0, 15, 30 or 45 min. The reactions were stopped by heating. The influence of their supernatants on glutamic acid decarboxylase activity in brain tissue was investigated. When 1 g of liver had been incubated with 1.17 or 1.75 μmol of crimidin for at least 30 min., the supernatant significantly reduced the decarboxylase activity; so did supernatants from 2.33 and 3.5 μmol of crimidin per g and this was already seen after 15 min. of incubation. Brain homogenate did not convert crimidin into a compound which could inhibit the decarboxylase activity within the reaction time.
Cortical and Striatal in Vivo Uptake and Metabolism of Plasma Choline in the Rat: Effects of Haloperidol and Apomorphine
Authors: Aquilonius Sten–Magnus , Eckernäs Sven–Åke
Published: July 2010

Abstract Following intravenous injection of a tracer dose of radioactive choline (3H–Ch), blood 3H–Ch was incorporated into parietal cortex at 1.2% per min. while the corresponding rate in the striatum was 6.4. It is suggested that this linear relationship in the time–interval 10 sec. to 20 min. following 3H–Ch injection demonstrates the in vivo existence of active uptake mechanisms of plasma Ch into brain. Furthermore, 36 % per min. of cortical 3H–Ch was converted to Ch metabolites other than acetylcholine (ACh) while the striatal percentage was only 6. This is probably due to the distribution of 3H–Ch into an “ACh–available” Ch pool within the cholinergic neurones which show the highest density in the striatum. Based on the present results and data in the literature a hypothetical scheme for the fate of brain Ch is discussed. The above mentioned parameters were also examined in cataleptic rats following haloperidol treatment (2 mg/kg intraperitoneally) as well as in rats slightly hyperactive following combined treatment with haloperidol (2 mg/kg intraperitoneally) and apomorphine (10 mg/kg intravenously). The results can be interpreted in the light of a dopaminergic inhibition on intrastriatal cholinergic neurones.
The Effects of some Anticholinergic Compounds on the Infused Urinary Bladder of Unanaesthetized Rabbits
Authors: Sjögren Christer
Published: July 2010

Abstract Three anticholinergic compounds, atropine, emeprone, and PR 197 (synthesized at AB Recip, Sweden), were tested for their effects on the infused urinary bladder of unanaesthetized rabbits. Following the injection of emeprone and PR 197 (1–4 mg/kg intravenously) the bladder volume capacity increased and the micturition pressure decreased. These drugs also produced a residual volume after micturition. No change in the micturition threshold pressure could be detected. Atropine (1–4 mg/kg intravenously) caused a marked decrease in the bladder volume capacity, micturition pressure, and micturition threshold pressure, but did not produce any residual volume. The results obtained in the present investigation using unanaesthetized animals differed from similar experiments, where anaesthetized animals were used. It is concluded that the peripheral actions of the substances used were confined mainly to the cholinergic receptors in the urinary bladder. The different response after atropine was attributed to its central stimulating effect.
Positive Inotropic Effect without Cyclic AMP Elevation after α–Adrenergic Stimulation of Perfused Hearts from Hypothyroid Rats
Authors: Osnes Jan–Bjørn
Published: July 2010

AbstractPrevious experiments suggested that the positive inotropic response to α–adrenergic stimulation was unrelated to cyclic AMP in contrast to the inotropic effect of β–adrenergic stimulation. In order to elucidate this question further we perfused hearts from rats made hypothyroid by treatment with propyl–thiouracil, since this treatment is known to augment the myocardial α–adrenergic effects. α–stimulation (phenylephrine in the presence of propranolol) caused a marked inotropic response and no increase in cyclic AMP. In contrast β–stimulation (isoprenaline) increased the cyclicAMPcontent. The time–courses of the inotropic responses to α– and β–stimulation were different. The aortic pressure waves indicated a shorter duration of each contraction phase after isoprenaline than after phenylephrine in the presence of propranolol. This difference is probably due to the cyclic AMP accumulated after isoprenaline. The findings support the hypothesis that the positive inotropic effect of α–adrenergic stimulation is caused by mechanisms independent of cyclic AMP, while the β–adrenergic inotropic effect involves cyclic AMP mediated processes. Such a dual mechanism of action for adrenergic agents might serve to maintain responsiveness of the heart under various conditions.
Enhancement of Hepatic Drug Metabolism with Dietary Cholesterol in the Rat
Authors: Laitinen Matti
Published: July 2010

Abstract The effect of dietary cholesterol on the biochemical composition and on the activities of drug metabolizing enzymes in the rat liver was studied. There were no statistically significant differences in the measured microsomal macrocomponents between the reference group on fat free diet and the experimental rats on 5 % cholesterol diet. However, there were marked changes in the fatty acid composition of microsomal phospholipids. The activities of cytochrome c reductase, cytochrome P–450 and p–nitroanisole o–demethylase were increased significantly during cholesterol feeding. The activitiy of aryl hydrocarbon hydroxylase remained unaffected. The activity of hepatic UDPglucuronosyltransferase was also increased very significantly with dietary cholesterol. It may be true that cholesterol affects the activities of drug metabolizing enzymes partly via changes in the membrane structure, but cholesterol may also act as an inducing compound.
Improvement of Oral Chelation Treatment of Methyl Mercury Poisoning in Rats
Authors: Gabard Bernard
Published: July 2010

Abstract Oral administration of sodium–2,3–dimercaptopropane–l–sulphonate leads to a substantially increased urinary excretion of intravenously injected methyl mercury in rat and proved to be clearly superior to equimolar doses of N–acetyl–D, L–homocysteinethiolactone and D–penicillamine.
Chlorinated Hydrocarbon Residues (PCB and DDT) in Human Liver, Adipose Tissue and Brain in Finland
Authors: Hattula Marja Liisa , Ikkala Jorma , Isomäki Matti , Määtta Kari , Arstila Antti U.
Published: July 2010

Abstract In this work the concentration of chlorinated hydrocarbons (PCB and DDT) was analyzed from 73 autopsy samples. Half of the material came from the coastal area of the Gulf of Bothnia and the other half from Central Finland. The correlation of the concentration of the drug to age, sex and the locality was studied as well as the occupation of the dead subjects.
Absorption and Elimination Kinetics of 32P Malathion in the Hen
Authors: Gupta P. K. , Paul B. S. , Ehrnebo M.
Published: July 2010

Abstract A method for the separation of urine and faeces in the hen was developed and the biological fate of 32P malathion, following a single oral dose of 262.40 mg/kg body weight was studied. The results suggested that the compound was rapidly absorbed from the gastrointestinal tract; significant quantities being detected in the plasma and whole blood 1/2 hr after ingestion. Total 32P was eliminated in the urine by apparent first order kinetics with an average half‐life of 5.7 hrs. The cumulative urinary and faecal data revealed that 93 % of the 32P is excreted via the urine within 48 hrs, thus indicating that the compound is almost completely absorbed. It is therefore concluded that accumulation in the system is unlikely.
Evoked Efflux of 3H‐Bretylium by Sympathomimetic Amines from the Rat Vas Deferens in Vitro
Authors: Ross Svante B. , Kelder Diana
Published: July 2010

Abstract The efflux of 3H‐bretylium in rat vas deferens in vitro evoked by a number of sympathomimetic amines was examined. The tissue was preloaded with 3H‐bretylium (2 × 1‐7 M) and the efflux of bretylium to the incubation medium in the presence of the amines during 20 rnin. was determined. The efflux evoked by (+)‐amphetamine was almost abolished at 0° and by desipramine. The dose response curves showed that some of the amines at high concentrations markedly antagonized their own effect. It could be demonstrated that (+)‐amphetamine and N‐methylamphetamine at a high concentration also antagonized the efflux evoked by low external Na+ concentration and it is suggested that this effect is produced by inhibition of the outward transport of bretylium through the neurone membrane. The structure activity relationship obtained shows that the non‐hydroxylated amines are most potent in evoking bretylium efflux and that the potency diminished with the number of hydroxyl groups. The tertiary amine analogue of amphetamine is less active and the quaternary derivative much less active than amphetamine and N‐methylamphetamine. A hydroxyl group at 3‐position gives a somewhat higher potency than that at 4‐position. This structure activity relationship is similar to that previously reported for the sympathomimetic amines in reversing the adrenergic neurone blockade by bretylium and it is proposed that this reversal is induced by the reduction of the intraneuronal concentration of bretylium as a result of the evoked efflux.
On the Absorption of Proscillaridin A after Single Oral Doses to Normal and Achlorhydric Subjects
Authors: Andersson K.‐E. , Bergdahl B. , Bertler Å. , Redfors A.
Published: July 2010

Abstract Proscillaridin A was given in single oral doses (1.5–2.5 mg) to normal and achlorhydric subjects. Plasma activities of the glycoside were analysed by 86Rb‐technique. The absorption pattern was similar in both groups. A marked first peak of proscillaridin activity was seen after about 30 min. After a first minimum, a second peak of activity was registered within 6–12 hrs. An estimate of the amount of active glycoside absorbed during the first 12 hrs after the administration was obtained by calculating the areas under the plasma activity curves (AUC). When corrected for differences in dose per kg body weight, the mean AUC in the achlorhydric group was about 60 % greater than in the normal group. The results suggest that proscillaridin is rapidly absorbed; gastric acidity seems to contribute to inter‐individual differences in the bioavailability of the glycoside.
The Pharmacology of a New Hypoglycaemic Agent N‐[4‐(2‐(2,3‐dihydrobenzo(b)furan‐7‐carboxamido)‐ethyl) ‐benzenesulphonyl] ‐N’‐cyclohexylurea (NOVO CS 476). I. Pharmacological Studies on the Hypoglycaemic effect
Authors: Jørgensen Karin Damm
Published: July 2010

Abstract The new sulphonylurea CS 476 has been shown to be a potent hypoglycaemic agent. In normal fasting dogs, rabbits, rats and mice the maximal hypoglycaemia produced by intravenous administration of CS 476 was comparable on a weight basis to that produced by glibenclamide. Randomized Latin square experiments in dogs showed that 0.03 mg/kg orally of CS 476 and of glibenclamide caused the same maximal decrease of blood glucose and that CS 476 had the shorter duration of action. CS 476 had no hypoglycaemic effect in totally pancreatectomized dogs nor in streptozotocin diabetic dogs and rats. The insulin releasing activity was studied in dogs after intravenous and oral administration of equipotent doses of CS 476, tolbutamide and glibenclamide. It was found that the insulin curves after CS 476 tended to have a plateau‐like maximum like those after glibenclamide although the duration of effect was shorter.
Activities of Proscillaridin A in Thoracic Duct Lymph after Single Oral Doses in Man
Authors: Andersson K.‐E. , Bergdahl B. , Dencker H. , Wettrell G.
Published: July 2010

Abstract In order to study the possibility that orally administered proscillaridin after absorption is transported by the lymph to the systemic circulation, the concentrations of the glycoside in thoracic duct lymph were analyzed in two patients with thoracic duct drainage. They received the drug as a single oral dose; plasma and lymph concentrations were measured by 80Rb‐technique. Lymph was collected at various intervals for 24 hrs. The proscillaridin activity in thoracic duct lymph was low and followed closely that in the plasma. During the sampling period, a total of 300 ng and 240 ng, respectively, was recovered in the lymph, corresponding to less than 0.03 %0 of the administered dose. The results indicate that proscillaridin is not transported by the thoracic duct lymph.
Plasma Levels and Electrophysiological Effects of Acebutolol (M & B 17.803) in the Dog Heartin Situ
Authors: Amlle Jan P. , Lessum Steen , Collins Raymond F. , Landmark Knud
Published: July 2010

AbstractThe effect of acebutolol a p‐adrenergic receptor blocking agent was tested on the dog heartin situ.The drug decreased heart rate, and caused a reduction in the conduction velocity and a significant increase in the functional refractory period of the atrioventricular node. The functional and the effective refractory period of the right atrium was increased by acebutolol. During sinus rhythm, the drug did not affect conduction velocity in the rest of the conduction pathway. During atrial pacing, however, the intra‐atrial and His‐Purkinje conduction times were slightly increased. The plasma concentrations of acebutolol were in the range between 0.09 and 0.5 μg/ml, which is far below those values expected to cause a membrane‐stabilizing or quinidine‐like effect. The clinical applications of the results are discussed.
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.
Penetration of delta‐9‐tetrahydrocannabinol and 11‐OH‐delta‐9‐tetrahydrocannabinol through the Blood‐brain Barrier
Authors: Schou Jens , Prockop Leon D. , Dahlström Gustav , Rohde Carsten
Published: July 2010

Abstract The relative brain uptake (extraction into brain) of delta‐9‐tetrahydro‐cannabinol (delta‐9‐THC) and the primary metabolite 11‐OH‐delta‐9‐tetrahydrocannabinol (11‐OH‐delta‐9‐THC) was measured after close intracarotid injection in rats of radiolabelled moities using labelled antipyrine as reference. The extraction percentage was of the same magnitude when injections were given in saline, 66 ± 11 % and 70 ± 9 % respectively after 5 sec., 59 ± 4 and 67 ± 8 respectively after 15 sec. While the extraction of 11‐OH‐delta‐9‐THC was the same when injected into plasma, the extraction of delta‐9‐THC was only about half of the extraction from saline, and also half the extraction of the metabolite from plasma. The higher uptake quantity of the metabolite into the brain may account for the relatively greater effect on the central nervous system of the metabolite than of the parent compound at equal concentrations in plasma. Moreover our experiments demonstrate that 11‐OH‐delta‐9‐THC formed in the liver after cannabis (delta‐9‐THC) administration may exert significant brain effects.
Passage of Digoxin into Cerebrospinal Fluid in Man
Authors: Allonen H. , Andersson K.‐E. , Iisalo E. , Kanto J. , Strömblad L.‐G. , Wettrell G.
Published: July 2010

AbstractThe passage of digoxin into the cerebrospinal fluid (CSF) was studied in 8 infants on maintenance therapy with digoxin, 11 adult patients on long‐term digoxin therapy, and 15 patients, previously non‐digitalized, who were given 0.5 mg digoxin orally 1 hr to 12 hrs prior to lumbar puncture. Digoxin in the serum and CSF was determined by radioimmunoassay. In the infants a mean serum concentration of 1.5 ng/ml (range 0.7‐2.3 ng/ml) was found, and a simultaneous mean CSF concentration of 0.5 ng/ml (range 0.3‐1.1 ng/ml). In the adults on long‐term therapy, the corresponding figures were 1.1 ng/ml (range 0.5‐2.2 ng/ml) and 0.3 ng/ml (range 0‐0.6 ng/ml). Among the 15 patients given a single oral dose of digoxin, detectable CSF concentrations (0.2‐0.3 ng/ml) were found in five, 1‐12 hrs after the administration of the drug. In three paediatric patients with hydrocephalus (3 months ‐ 5 years) digoxin therapy was started as an attempt to decrease CSF production. In these patients, the production of CSF was reduced by 17, 25 and 30 %, respectively.
Inhibition of Prolactin Secretion and Synthesis by Dopamine, Noradrenaline and Pilocarpine in Cultured Rat Pituitary Tumour Cells
Authors: Bang Sverre , Gautvik Kaare M.
Published: July 2010

Clonal strains of rat pituitary tumour cells (GH3‐cells) synthesize and secrete prolactin into a chemically defined culture medium. Short time treatment (0.5–2 hrs) of cell cultures with noradrenaline (10‐3 M) and dopamine (10‐3 M) reduced the spontaneous secretion of prolactin by 50 % and 30 %, respectively, while pilocarpine (10‐3 M) had no effect. Long‐term treatment (20 hrs) with noradrenaline (10‐3 M) or with pilocarpine (10‐3 M) inhibited prolactin synthesis by 45 % and 65 % of control cultures, respectively, Neither compounds affected cell growth. The inhibitory effect of noradrenaline, but not that of pilocarpine, was completely reversed 4 hrs after cessation of treatment. Adrenaline, dopamine and acetylcholine in concentrations up to 10‐3 M did not change prolactin synthesis. In contrast thyroliberin treatment (2×10‐8 M) caused a 45 % increase in prolactin secretion, and resulted in a 40 % increase in hormone synthesis after treatment for 20 hrs. It is concluded that both noradrenaline and dopamine are able to inhibit prolactin secretion. Prolactin synthesis could be inhibited by noradrenaline and pilocarpine. However, only the effect of noradrenaline is easily reversible on cessation of treatment.
Dextran‐Induced Lowering of Prekallikrein Proactivator and Prekallikrein in Rat Plasma
Authors: Briseid Gudrun , Briseid Kjell , Toverud Else‐Lydia , Kristoffersen John
Published: July 2010

Abstract The intravenous injection into rats of dextran (average M W 70,000) 10 mg/100 g caused marked hypotension after a delay of about 5 minutes. Blood samples collected by cardiac puncture at this time were tested for the amounts of prekallikrein activator (PKA) and kallikrein after acetone‐ and then kaolin activation of the plasminogen‐free plasma. PKA was assayed by measuring the initial rate of release of benzoyl arginine esterase (BAEe) activity in a preparation of partially purified human prekallikrein, and kallikrein was assayed by measuring the BAEe esterase activity. Significant reductions of both parameters were registered, and the amount of high molecular weight kininogen (HMWK) present in the plasma was also reduced. Pretreatment of the rats with ε‐aminocaproic acid intraperitoneally (200–300 mg/100 g) abolished the dextran‐caused decreases in the plasma levels of the above mentioned factors, and reduced the fall in blood pressure. The addition of purified human HMWK to the plasma before the acetone activation procedure was started, increased the yield of PKA activity in the final enzyme preparation. When PKA was assayed after kaolin activation of plasma at 0° using the method developed by Laake & Vennerød (1973a & b) for the determination of PKA (activated factor XII) in human plasma, no differences were registered between plasma from rats treated with dextran and plasma obtained from control rats. It is suggested that the low PKA activity of the acetone activated enzyme preparation from plasma of rats treated with dextran was due to the loss of HMWK or a fraction of HMWK.
Measurement of Plasma and Erythrocyte Chlorpromazine and N‐Monodesmethylchlorpromazine Levels by Gas Chromatography with a Nitrogen Sensitive Detector
Authors: Linnoila M. , Dorrity F.
Published: July 2010

Abstract A new gas chromatographic method, employing a nitrogenphorphorus sensitive detector, for the measurement of chlorpromazine and N‐monodesmethylchlorpromazine is described. The application of the method to the measurement of the drugs in clinical plasma and erythrocyte samples is demonstrated. It was found that the chlorpromazine concentration in the erythrocytes is positively and linearly correlated with the drug level in the plasma. However, a 4‐fold inter‐individual variation in the erythrocyte/plasma concentration ratios was evident. The concentration of the metabolite in the erythrocytes was found to be up to 27% of that of the parent compound. Chlorpromazine was unstable in plasma but stable in erythrocytes during a week's storage in the dark at ‐20°. The possible clinical implications of our findings are discussed.
Glutathione Turnover in Isolated Hepatocytes
Authors: Högberg J. , Kristoferson A.
Published: July 2010

Abstract Isolated hepatocytes lost about half their content of GSH when treated in vitro with 90 nmol of diethylmaleate per 106 cells. Within one hour GSH started to accumulate in the cells, and the rate of accumulation was taken as a measure of the GSH synthesis rate. The rate was affected by additions of amino acids and horse serum to the incubation medium. The methionine and cysteine uptake rates were much lower than the rate of GSH synthesis and not affected by variations in the GSH synthesis rate. The methionine and cysteine uptake rates were not affected by horse serum. It is concluded that even though exogenous sulphur‐containing amino acids facilitate GSH synthesis, the hepatic cysteine pool is to a large extent replenished by endogenous amino acids derived from protein degradation. In particular, this is the case when the turnover rate of the cysteine pool is increased by drug metabolism.
Terbutaline Preventing Permeability Effects of Histamine in the Lung
Authors: Persson C. G. A. , Ekman M. , Erjefält I.
Published: July 2010

Abstract In unanaesthetized guinea‐pigs the effect of terbutaline on histamine‐induced increase in lung weight was studied. Terbutaline 0.1 mg/kg and 0.3 mg/kg was given subcutaneously 5 min. before exposure during 60 min. to a histamine aerosol. Terbutaline markedly prevented the histamine‐induced increase in lung weight. This effect is discussed in relation to the mechanism of action for mediator‐induced increase in vascular permeability.
Effects of DDT (Chlorophenotane) Administration on Glucose Uptake and Brush Border Enzymes in Monkey Intestine
Authors: Mahmood A. , Agarwal N. , Sanyal S. , Subrahmanyam D.
Published: July 2010

Abstract A considerable increase occurs in D‐glucose uptake and brush border sucrase and lactase activities in the intestine of monkeys treated with a single oral dose of DDT. Brush border alkaline phosphatase activity remains unaffected in the pesticide treated animals. In vitro addition of DDT has no effect on the sugar absorption and disaccharidase activities.
Effects of Nifedipine on the Smooth Muscle of the Human Urinary Tract in Vitro and in Vivo
Authors: Forman A. , Andersson K.‐E. , Henriksson L. , Rud T. , Ulmsten U.
Published: July 2010

Abstract Smooth muscle preparations of the urethra, bladder, and ureter were obtained from patients undergoing operations for various urological disorders. The urethral preparations were contracted by noradrenaline (0.1–3 μg · ml‐1), prostaglandin F2α (1–10 μg · ml‐1), and potassium (127 mM), the bladder preparations by carbacholine (0.004–1 μg · ml‐1), prostaglandin F2α (1–10 μg · ml‐1), potassium (127 mM), and barium chloride (3 mM), and the ureter preparations by potassium (127 mM), and barium chloride (3 mM). Irrespective of the mode of activation, pretreatment with nifedipine (0.1 μg · ml‐1) for 10 min. reduced the responses. Nifedipine also relaxed preparations contracted by the contractile agents used.

In 19 female patients, aged 20 to 73 years, undergoing investigation because of urgency and/or urge incontinence, simultaneous urethrocystometry at rest was performed before and after oral administration of 20 to 40 mg nifedipine. Bladder capacity and residual urine were also determined. Nifedipine did not affect the pressures within the bladder and urethra, nor did it increase the bladder capacity. However, after nifedipine intake there was a statistically significant increase in residual urine. The results suggest that nifedipine can inhibit contractile activity induced by drugs with different modes of action; the drug does not affect the tone in bladder and urethra.
Interaction of Vitamin E and Selenium with the Hepatotoxic Agent Dimethylnitrosamine
Authors: Skaare Janneche Utne , Nafstad Inger
Published: July 2010

Abstract Pretreatment of rats with vitamin E, 0.02% w/w of the diet and a sc dose, 200 mg/kg, given 48 hrs. before dimethylnitrosamine, DMNA, was found to ameliorate the acute hepatotoxicity of DMNA (30 mg/kg) as reflected in reduced plasma asparagine‐amino‐transferase (AspAT) activity. This effect was confirmed by histological evaluation. No significant effect of DMNA on plasma levels of vitamin E was observed, however, DMNA significantly increased the hepatic level of vitamin E supplemented rats. Pretreatment with selenium, 0.5 mg/kg given intraperitoneally 48 hrs. before DMNA, was found to enhance the acute hepatotoxicity of DMNA as reflected in increased elevation of plasma AspAT activity. This effect was not confirmed morphologically. DMNA did not have any effect on the hepatic selenium state in selenium pretreated rats; however, selenium pretreatment tended to decrease hepatic and plasma tocopherol levels. To explain the effects observed in the present investigation, various mechanisms were discussed.

If the compounds were acting as antioxidants, then the difference in intracellular localization had to be important. More likely a specific biochemical function involving drug metabolizing enzymes could be involved. Finally vitamin E could protect membranes from damage during the necrotizing action of DMNA.
Excretion of Intravenously Injected Copper‐64 in Sheep
Authors: Søli Nils E. , Rambæk Jon P.
Published: July 2010

Abstract Copper‐64 was injected intravenously into three sheep. The total excretion of copper in sheep was low since only 1.4‐1.7% of the dose injected was excreted during a period of 60 hrs. following the injection. It was found that the biliary system was not a main excretory pathway for copper; other routes of excretion into the gastrointestinal tract seemed to be more important. The urinary and the biliary excretion were of comparable magnitude. The activity in the bile was found to be lower than in the plasma throughout the sampling period. It is assumed that a low excretion capacity of copper in the bile of sheep may be a possible factor of importance for the high susceptibility of this species to excess of copper.
Increased Penetration of Barbital through the Bloodbrain Barrier in the Rat after Pretreatment with Probenecid
Authors: Wahlström Göran
Published: July 2010

AbstractSome weak organic acids are eliminated from the brain by an acid transport system. The question arose is this system also used to transport drugs out of the brain? In that case probenecid pretreatment (100 mg/kg subcutaneously) should influence the induction time of a slightly lipid soluble barbiturate (barbital) which penetrates into the brain slowly, more than the induction time of a very lipid soluble barbiturate (hexobarbital). In the first experiment barbital (200 mg/kg) was given intraperitoneally and in the second experiment barbital (150 mg/kg) was infused intravenously during 10 min. In both experiments loss of righting reflex occurred more rapidly after pretreatment with probenecid compared with pretreatment with saline. Only in the second experiment did probenecid significantly increase the time during which the righting reflex was lost. In the next experiment hexobarbital was infused intravenously at a rate of 0.25 mg/kg/sec. until a burst suppression which lasted 1 sec. or more was seen in a concomitant EEG‐record. When this »silent second« occurred the infusion was stopped and the ensuing anaesthesia times recorded. Probenecid had no effect on the induction when studied with this method, but the ensuing anaesthesia times were increased. The hypothesis of an acid transport system out of the brain was thus not refuted by these experimental results. Studies of brain concentrations of barbital also supported this finding. After 200 mg/kg intraperitoneally the concentration of barbital in the brain was higher after pretreatment with probenecid as compared to saline pretreated controls i.e. at times corresponding to the induction times in the in vivo experiments. No difference was found in the serum levels of barbital.
Distribution of [14C]‐Labelled Aflatoxin B1 in Mice
Authors: Arora R. G. , Appelgren L.‐E. , Bergman A.
Published: July 2010

Abstract The distribution of [14C]‐labelled aflatoxin B1 has been studied in mice with the aid of whole‐body autoradiography. In addition to the localisation of labelled aflatoxin B1 and/or its metabolites in the liver, bile, kidney, lung and urine an uptake of 14C in the pigment of the Harderian gland and the eye was observed. Uptake of radioactivity was also found in the eyes of the foetuses although their livers did not accumulate radioactivity.
Transient Supersensitivity in the Partially Denervated Urinary Bladder of the Rat
Authors: Ekström Jörgen , Elmér Mats , Banns Heather
Published: July 2010

Abstract When examined 6–7 days after the unilateral removal of the pelvic ganglion, the detrusor muscle of the rat was found to be sensitized to methacholine and noradrenaline. The threshold doses were lower while the intravesical pressure responses to doses above threshold were increased. In contrast, bladders examined 25–30 days after the partial denervation lacked signs of sensitization. It is suggested that the contralateral nervous pathway is responsible for the rapid disappearance of the supersensitivity.
Alpha‐Adrenolytic Treatment in Patients With Autonomous Bladders.
Authors: Norlén Lars , Sundin Torsten
Published: July 2010

Abstract The effect of alpha‐adrenolytic treatment (phenoxybenzamine) was studied in 8 patients with lower motor neuron lesions (autonomous bladders). In the cystometrograms, the bladders were more hypotonic and the “autonomous waves'’ appeared at a higher level of filling or were totally extinguished after this pharmacological treatment. With an isotonic volume registration method, a bladder volume increase was recorded after alpha‐adrenergic blockade. Using spincterometry or urethral pressure profile studies, a decrease in the urethral resistance was observed after alpha‐adrenolytic treatment, resulting in a decrease in residual urine. This decrease in bladder wall tension and in residual urine effected an increased functional bladder capacity in patients with autonomous bladders.
The Effects of Anticholinergics on the Urinary Bladder Mechanism.
Authors: Sjögren Christer
Published: July 2010

AbstractA summary is given of the physiological conditions concerned with collection and expulsion of urine from the bladder. The role of afferent and efferent nerve activity from and to the urinary bladder and urethra is discussed. When studying the effects of anticholinergics on the urinary bladder in animals anin situmodel described here seems to be the most valid for conditions in man. This method involves recording of the intravesical pressure in conscious rabbits simultaneously with a bladder infusion. An assessment is made of the evidence for a purinergic transmission in the urinary bladder.
90Sr in Placentas, Embryos and Foetuses of Mice, Evaluated by Whole‐Body Autoradiography
Authors: Olsen Ingar , Jonsen Jon
Published: July 2010

Abstract 90Sr is a hazardous fission product from nuclear reactions. Its transplacental passage is of particular interest because of the high sensitivity of embryos/foetuses to ionizing radiation. We have used whole‐body autoradiography to study the foetal uptake and retention of 90Sr and the embryonic/foetal transfer of this isotope as a function of gestational age. Fifteen minutes after an intraperitoneal injection of 50 μci 90Sr‐nitrate into a 14‐day‐pregnant mouse, radioactivity was present in the placenta, but not in the foetus. During a 72‐hour observation period, 90Sr gradually accumulated in the hard foetal tissues. In the soft foetal tissues, accumulation occurred up to 12‐24 hours. After 72 hours, no 90Sr could be detected in the soft tissues. 90Sr crossed the visceral yolk sac placenta during early gestation, the visceral yolk sac and the chorioallantoic placentas during late gestation. Transfer increased considerably at the end of the latter period. There was a marked uptake of 90Sr in all structures of early embryos, whereas the isotope concentrated in the preskeletal and skeletal parts of the foetuses. Intake of 90Sr during early gestation may therefore be more injurious to the offspring than intake during late gestation.
Effect of Cadmium Acetate, Copper Sulphate and Nickel Chloride on Organ Cultures of Mouse Trachea
Authors: Olsen Ingar , Jonsen Jon
Published: July 2010

Abstract Tracheas from albino mice were excised and cut into rings approximately 1 mm thick. After pre‐incubation overnight in Medium 199 with 5% calf serum, they were placed into fresh medium. Cadmium acetate, copper sulphate or nickel chloride was added separately or in combination, to a final concentration of 10‐200 μM. Each metal was also added (10 μM) to serum‐free Medium 199. The percentage (0‐100) of the inner intact epithelium and the rate (0‐4) of the ciliary beat in each ring were assessed before and during a 4‐hour incubation period and multiplied to yield a relative activity index (0‐400). Cadmium acetate at 10‐100 μM depressed the ciliary activity significantly more than 10‐100 μM copper sulphate (each level P<0.05). With 200 μM a 50% reduction of the activity index was observed after approximately 35 min. with cadmium acetate and 85 min. with copper sulphate. At 10‐200 μM, cadmium acetate was significantly more suppressive than nickel chloride (each level P<0.05). When comparing the inhibitory effects of copper sulphate and nickel chloride a significant difference appeared at 10‐100 μM (each level P<0.01), but not at 200 μM (P>0.05). With 200 μM nickel chloride a 50% reduction in the activity index was observed after 90 min. There was a tendency towards reduced toxicity of cadmium acetate when combined with copper sulphate and of copper sulphate when combined with nickel chloride. In serum‐free medium metal toxicity was increased.