bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Pure Chlorobiphenyls (2,4′,5 ‐ trichlorobiphenyl or 2,2′,4,4′,5,5′‐ hexachlorobiphenyl) on the Disappearance of14C from the Blood Plasma after Intravenous Injection of 4‐14C‐progesterone and on the Hepatic Drug Metabolizing System in the Female Rat
Authors: Örberg Jan , Ingvast Carina
Published: July 2010

AbstractEffects of two pure chlorobiphenyls (2,4′,5‐trichlorobiphenyl or 2,2′,4,4′,5,5′‐hexachlorobiphenyl) on the hepatic drug metabolizing system and on the elimination rate of14C from the blood after intravenous injection of 4‐14C‐ progesterone have been studied in the female rat. The results obtained show that females pre‐treated with small amounts of 2,2′,4,4′,5,5′‐hexachlorobiphenyl (0.5 mg/day for 14 consecutive days) have significantly higher elimination rates of14C (originating from intravenous injection of 4‐14C‐progesterone) from the blood plasma, significantly higher content of hepatic cytochrome P‐450 and significantly heavier livers than control females. On the other hand, the results obtained from females pre‐treated with small amounts of 2,4′,5‐trichlorobiphenyl (0.5 mg/day for 14 consecutive days) do not differ significantly from the results obtained from control females.
Evidence for Two Catalytically Different Binding Sites of Liver Microsomal Cytochrome P‐450: Importance for Species and Sex Differences in Oxidation Pattern of Lidocaine
Authors: von Bahr Christer , Hedlund Inger , Karlén Bo , Bäckström Dan , Grasdalen Hans
Published: July 2010

AbstractWhen the local anaesthetic drug lidocaine is added to liver microsomes biphasic type I spectral change titration curves can be observed. A high‐affinity and a low‐affinity phase is observed. In the present study we have found that microsomes from female rats have a dominant high‐affinity phase, which can hardly be observed within microsomes from female guinea pigs. Male rats showed an intermediate phase. On incubation of lidocaine at concentrations of 1 γM or less with female rat liver microsomes a larger fraction of the drug was aromatically hydroxylated than deethylated. The opposite was true for guinea pig liver microsomes, and microsomes from male rats were intermediate. The ratio between the formation of deethylated and hydroxylated metabolites increased with the lidocaine concentration and at a lidocaine concentration of 10‐4M deethylation was the dominant oxidation type in all microsomes. The data suggest that the two spectral phases represent two binding sites of cytochrome P‐450 each having a certain “catalytic specificity” ‐ the high affinity catalyzing aromatic hydroxylation and the “low‐affinity site” deethylation. This hypothesis is further supported by the observed differential effects of pH and MgCl2concentration on the two types of oxidation.
Influence of Serum Protein Binding on the Pharmacokinetics of Quinidine in Normal and Anuric Rats
Authors: Fremstad Dag , Jacobsen Sten , Lunde Per K. M.
Published: July 2010

AbstractThe pharmacokinetics of quinidine were investigated in normal and anuric rats after intravenous injection (25 mg per kg b. wt.). In normal rats only 2.6 percent of the injected dose was excreted as unchanged quinidine in the urine. Quinidine concentrations were determined in the blood and in different tissues after injection, and the serum protein binding was measured. Results were applied to a one compartment model. In normal rats a total body clearance of 18.5 ml/min. and a renal clearance of 0.5 ml/min. was found. The residual non‐renal clearance (18.0 ml/min.), presumably taking place in the liver, exceeds the estimated liver blood flow (16.8 ml/min.), indicating efficient extraction of quinidine from plasma and blood cells (non‐restrictive elimination). The apparent volume of distribution was greatly reduced, biological half‐life slightly longer and the body clearance greatly reduced in anuric as compared to normal rats. The fraction of unbound quinidine in serum was 30.6 ± 0.6 (n=23) and 16.7 ± 0.5) (n=23) percent in normal and anuric rats. The reduction in the apparent volume of distribution is mainly explained by increased serum binding. The decline of body clearance of quinidine is most likely caused by a decreased liver blood flow in this complex state of renal insufficiency.
Carbamazepine: Placental Transport, Tissue Concentrations in Foetus and Newborn, and Level in Milk
Authors: Pynnonen S. , Kanto J. , Sillanpää M. , Erkkola R.
Published: July 2010

Abstract The pharmacokinetics of carbamazepine were studied during pregnancy and early childhood by investigating the extent of its placental penetration and its distribution in the foetal and neonatal tissues at autopsy. In foetuses the liver and kidney contained high levels of carbamazepine, whereas brain and lungs had low values. Carbamazepine‐10,11‐epoxide was also detected in the foetal circulation. At autopsy material, carbamazepine was localized mostly in the cerebral cortex, heart, liver and kidney. The concentration of carbamazepine in the milk was found to be 60 per cent of the respective plasma value.
Local and Systemic Effects of Commonly Used Cutaneous Agents: Lifetime Studies of 16 Compounds in Mice and Rabbits
Authors: Stenback Frej
Published: July 2010

AbstractA number of commonly used external agents were applied repeatedly on the skin of the mouse and rabbit. These chemicals, components of commercially available products included 4‐hydroxyanisole, benzalkonium chloride, bromodeoxyuridine, iododeoxyuridine, 5‐nitroacenaphthene, N‐N‐diethyltoluamide, hexachlorophene, para‐aminobenzoic acid, benzophenone, isopropylmyristate, pyrogallol, resorcinol and ethylhexanediol. Also tested were a commercial hairspray, a dandruff shampoo and an anti‐dandruff agent. Local and systemic changes were studied and the tumour incidence compared with that of an effective carcinogen, 9,10‐dimethylbenz(a)anthracene. The mice showed no local toxic changes or tumour formation and the systemic tumour incidence, i. e., tumours of the liver, lungs, lymphatic system and other organs, was similar to that of control animals. In rabbits, a number of proliferative, benign and malignant ear tumours were observed in the positive controls, thereby demonstrating the efficiency of this model. Local toxic changes were seen in benzalkonium‐ and hexachlorophene‐treated animals, but no skin tumours. Four animals had uterine tumours. In addition, one lung and one kidney tumour, unrelated to the method of treatment, were seen.
Correlations between Serum Ami‐ and Nortriptyline Concentrations and Psychomotor Performance
Authors: Seppäiä T. , Liljequist R. , Linnoila M. , Overa K. Fredricson , Dorrity F.
Published: July 2010

Abstract Correlations of serum nortriptyline (NT) and amitriptyline (AT) levels with psychomotor performance choice reaction performance, eye‐hand coordination, and divided attention was studied in two experiments each with 20 healthy subjects. In the first experiment serum NT level was measured with an isotope derivative method after treatment for 14 days with NT. In the second trial plasma AT and NT concentrations were measured with gas‐chromatography after treatment for 14 days with AT. No linear correlations between the levels of the antidepressants and performance variables were found. Low levels of NT (< 50 ng/ml) tended to shorten reaction time, and intermediate levels (50‐80 ng/ml) to prolong it, when compared with the reaction times during placebo. The correlation between serum NT levels and the increase of the tyramine dose in the tyramine pressor test was not significant. A new assay method for AT and NT is presented.
Selective and Non‐Selective Beta‐Blockade in Renin Release
Authors: Lammintausta R. , Syvähihti E. , Iisalo E. , Kanto J. , Mäntylä R.
Published: July 2010

Abstract The effects of two beta‐adrenergic receptor blocking drugs, the non‐selective propranolol and the beta1selective metoprolol, were studied on hemodynamics and plasma renin activity (PRA) of healthy volunteers in an ergometric exercise test. Oral doses of 160 mg of propranolol and 200 mg of metoprolol were tested against placebo. The drug plasma concentrations were determined. Heart rate and systolic blood pressure were equal and significantly lower during treatment with both active drugs when compared to placebo. The effect of drugs on exercise heart rate was correlated with the logarithm of drug plasma concentration with both propranolol and metoprolol. Propranolol, but not metoprolol, decreased the basal level of PRA. The ergometric exercise induced a significant rise in PRA after placebo but this increase was partially inhibited by the both active drugs. On the basis of these findings it is suggested that in man the basal level of PRA could be decreased mainly by blocking the beta2‐adrenoceptors. Instead the exercise induced increase of PRA could be inhibited by blocking the beta1‐adrenergic receptors.
Mechanical and Metabolic Effects of Diazoxide in Rat Uterus
Authors: Johansson S. , Andersson R. G. G. , Wikberg J.
Published: July 2010

AbstractDiazoxide relaxed both polarized and depolarized rat uterus. The drug also counteracted the contractions elicited by Ca2+in a competitive manner. The relaxing effect was associated with an increase in the tissue level of cyclic AMP. This metabolic effect of diazoxide was inhibited by propranolol‐treatment and in preparations from reserpinized animals, while the mechanical effects were only partially reduced. Diazoxide was also found to increase the release of tritium from preparations preloaded with [3H]‐noradrenaline. It is suggested that diazoxide may induce some of its mechanical and metabolic effects by releasing the adrenergic transmittor substance noradrenaline. An effect of diazoxide on the Ca2+‐metabolism is also probable.
Respiratory and Cardiovascular Effects of 3‐MethyIxanthine, a Metabolite of Theophylline
Authors: Persson C. G. A. , Andersson K.‐E.
Published: July 2010

Abstract:The effects of 3‐methylxanthine (3‐MX), a major metabolite of theophylline in man, were studied and compared with those of theophylline in isolated preparations of human and guinea‐pig airways, isolated guinea‐pig hearts, and in anaesthetized cats. 3‐MX was pharmacologically active, producing effects similar to those of theophylline. The guinea‐pig and human airways preparations were relaxed; the rate and force of contraction of guinea‐pig hearts were increased. In anaesthetized cats, 3‐MX decreased the respiratory overflow and arterial blood pressure, and increased the heart rate. Theophylline was always more potent (between 1 and 5 times) than 3‐MX. It is suggested that 3‐MX may contribute to the effects of theophylline during long‐term treatment.
Qualitative Differences between β‐Adrenergic and α‐Adrenergic Inotropic Effects in Rat Heart Muscle
Authors: Osnes Jan‐Bjørn , Refsum Helge , Skomedal Tor , Øye Ivar
Published: July 2010

AbstractIf β‐ and α‐adrenergic inotropic effects are cyclic AMP dependent and cyclic AMP independent, respectively, they may be qualitatively different. The inotropic effects of β‐receptor stimulation (isoprenaline) and α‐receptor stimulation (phenylephrine combined with propranolol) were characterized in isolated perfused rat hearts, rat atria and rat papillary muscles. The β‐effect reached its maximum before the α‐effect. The α‐effect followed a three‐phasic time‐course indicating both stimulatory and inhibitory components. The aortic pressure wave (perfused heart) indicated a shorter contraction phase after β‐stimulation than after α‐stimulation. The time to peak tension (atrium, papillary muscle) was relatively shorter after isoprenaline than after α‐stimulation, which tended to prolong it. The contraction‐relaxation cycles (atrium, papillary muscle) were examined by recording the isometric tension (T), its first (T′) and second (T″) derivatives, α‐ and β‐stimulation both increased Tmax, T′max(maximal rate of tension rise), T′min, (maximal rate of tension decline) and T″min(maximal rate of transition from rise to decline of tension). Isoprenaline increased Tmin, (papillary muscle) and T″min(atrium, papillary muscle) relatively more than did α‐stimulation, i.e. the relaxing processes were activated relatively more by β‐stimulation. The results indicate different mechanisms for the two adrenergic inotropic effects. The relatively larger activation of relaxation by β‐stimulation is assumed to be caused by cyclic AMP.
Lithium Neurotoxicity. I. The Concentration of Lithium in Dopaminergic Systems of Rat Brain Determined by Flameless Atomic Absorption Spectrophotometry
Authors: McGovern A. J. , Makanjuola R. , Arbuthnott G. W. , Loudon J. B. , Glen A. I. M.
Published: July 2010

Abstract Severe neurotoxicity has been reported in patients receiving combinations of lithium and butyrophenones and halogenated phenothiazines and the suggestion has been made that lithium is preferentially concentrated in dopamine systems in brain. Conventional flame atomic absorption spectrophotometry does not allow analysis of sufficiently small samples of brain tissue to allow accurate association with specific transmitter systems, although previous reports have suggested that lithium is concentrated in the striatum. A method has been developed using flameless atomic absorption spectrophotometry to allow accurate measurement of lithium concentrations in 10–100 ng amounts in less than 10–100 mg fresh weight of brain tissue. Using this technique in experiments where rats were fed lithium over a period of three weeks, we could not confirm a direct association of lithium with an area predominently served by dopamine transmitters.
The Effect of Nifedipine on the Sinus and Atrioventricular Node of the Dog Heart after β‐Adrenergic Receptor Blockade
Authors: Amlie Jan P. , Landmark Knud
Published: July 2010

Abstract The effect of nifedipine (BAY 1040), a calcium‐antagonistic inhibitor of the electromechanical coupling process was tested on atrioventricular conduction and refractoriness of the dog heart in situ by means of His‐bundle electrography and programmed electrical stimulation. The animals were anaesthetized with sodium pentobarbital. As the basic effects of the compound can be altered by release of catecholamines from sympathetic nerves of heart and vessels, the dogs were pretreated with acebutolol, a β‐adrenergic receptor blocking agent, which decreased heart rate and prolonged atrioventricular conduction and refractoriness. Nifedipine 1,6 and particularly 30 μg/kg body weight increased the heart rate and decreased atrioventricular conduction time during atrial pacing, whereas atrioventricular conduction time during sinus rhythm and atrioventricular refractoriness were only affected by nifedipine 30 μg/kg. In this respect, nifedipine differs distinctly from another calcium antagonistic compound, verapamil.
Myocardial Effects of Lithiumin Vitro
Authors: Nielsen‐Kudsk F. , Pedersen A. Kirstein
Published: July 2010

AbstractThe myocardial effects of increasing concentrations of ionic lithium were investigated in isolated, spontaneously beating rabbit hearts, which were retrogradely perfused with a modified Krebs‐Henseleit solution containing lithium in concentrations of 1, 5 or 10 mM. The following functional parameters were continuously recorded: heart rate, amplitude and rate of contraction, coronary flow, myocardial oxygen consumption and ECG. The lowest concentration of 1 mM lithium did not cause any measurable changes in these parameters. A concentration of 5 mM lithium produced a rather slowly developed increase in amplitude and rate of contraction of about 22% without any concomitant increase of oxygen consumption. A delayed increase in the oxygen consumption of about 21%, but accompanied by a significant decrease in contractility however, occurred much later in the experiments, probably as an expression of a decrease in myocardial efficiency. The highest lithium concentration produced similar effects. None of the other parameters measured were markedly influenced by lithium. The positive inotropic effect of lithium on myocardial contractility was very convincingly verified in isolated electrically stimulated rabbit papillary muscles by isometric measurements of the maximum tension produced and the rate of its development. An inhibitory influence of lithium on the positive inotropic effect of increasing frequency of stimulation was observed. Adrenergic β‐receptor blockade did not abolish the positive inotropic effect of lithium. A possible causative influence of lithium on the cellular calcium metabolism is discussed.
Effect of (+)‐Amphetamine on the Retention of 3H‐Catecholamines in Slices of Normal and Reserpinized Rat Brain and Heart
Authors: Ross Svante B. , Renyi Anna L.
Published: July 2010

Abstract The effect of reserpine on the inhibition by (+)‐amphetamine and cocaine of the accumulation of 3H‐dopamine (DA) in striatal slices and 3H‐noradrenaline (NA) in slices of cerebral occipital cortex and heart atrium of rats and the release of the 3H‐amines from these tissues were examined. Reserpine (5 mg/kg intraperitoneally) was injected 18 hours before the experiments. It was found that reserpine markedly enhanced the in vitro potency of amphetamine in the striatum and heart but only slightly in the cortex. After administration in vivo (+)‐amphetamine was about 10 times more potent in reducing the amine accumulation in the cortex as in the striatum. Reserpine enhanced the effect in both regions. The inhibitory potency of cocaine in vitro was unchanged by reserpine in the striatum but was reduced in the cortex and heart. Reserpine did not change the inhibitory potency of desipramine in the cortex and heart. The release of the 3H‐amines by (+)‐amphetamine was enhanced by reserpine in the striatum and heart but the small release produced in the cortex was not increased. The release produced by cocaine was similarly enhanced by reserpine but cocaine was much less active than (+)‐amphetamine. The results indicate that (+)‐amphetamine and cocaine inhibit the amine accumulation by different mechanisms.
Effects of Isoprenaline on the Time Course of the Cyclic AMP Level in Rat Uterus
Authors: Johansson Solveig R. M. , Andersson Rolf G. G.
Published: July 2010

AbstractIsoprenaline markedly relaxed rat uterine muscle and increased its content of cyclic AMP. The cyclic AMP concentration reached its highest value, about ten times the control after 3 min., after which it declined rather quickly at first but later more slowly. After 60 min. the cyclic AMP content reached twice the prestimulation value. The muscle remained relaxed all the time. If the incubation medium from the uterus treated with isoprenaline for 60 min. was added to a fresh muscle, a normal response was elicited. Addition of a new dose of isoprenaline to a muscle previously incubated with isoprenaline for 60 min. only gave a minimal rise in cyclic AMP after 3 min. The presence of catechol or corticosterone, which both decreased the inactivation of isoprenaline, showed no effect on the decrease of the isoprenaline‐stimulated cyclic AMP level. Nor could the decrease in the cyclic AMP response be prevented in the presence of GTP, F‐, adenosine or in Ca2+‐deflcient medium. The addition of theophylline and puromycin both lead to a slower decline of cyclic AMP content, but after 60 min. the value returned to near that seen after only isoprenaline. Our studies on isoprenaline‐induced desensitization of rat uterus have led us to the conclusion that the change in the capacity of the preparations to accumulate cyclic AMP may be a result of either changes in the β‐adrenoceptors or in the cyclase‐system.
Experimental Anti‐Arrhythmic Properties of Melperone, a Neuroleptic Butyrophenone
Authors: Petersen Erling N.
Published: July 2010

AbstractThe neuroleptic butyrophenone, melperone, has been compared with antiarrhythmics, neuroleptics, α‐blockers and β‐blockers in various experimental arrhythmias. Melperone 0.01–1 mg/kg intravenously antagonized ouabain‐induced arrhythmias in conscious rabbits to the same degree as propranolol 2 mg/kg and quinidine 10 mg/kg intravenously probably mainly via a CNS depressive effect. It was found to be considerably weaker than propranolol 2 mg/kg, when anaesthetized guinea pigs were used. Melperone 0.1–10 mg/kg was inactive against aconitine‐induced arrhythmias. Melperone 1–5 mg/kg antagonized adrenaline‐induced arrhythmias in halothane‐sensitized guinea pigs like phentolamine 1–5 mg/kg intravenously and was more potent than chlorpromazine, propranolol and quinidine. This study and an electrophysiological study suggest that melperone might be a type III anti‐arrhythmic drug, which at the same time depresses CNS and reduces afterload.
A Comparative Study on the Effects of Disulfiram, Cyanamide and 1‐Aminocyclopropanol on the Acetaldehyde Metabolism in Rats
Authors: Marchner H. , Tottmar O.
Published: July 2010

Abstract1‐aminocyclopropanol (ACP) is a potent inhibitor of aldehyde dehydrogenase (ALDH)in vivoandin vitro.Like cyanamide it has a rapid onset of actionin vivowith the highest inhibition occurring after 2‐24 hrs. and a long duration of action like disulfiram with measurable inhibition after 144 hrs. All the three inhibitors decreased the activity of the mitochondrial low‐KmALDH stronglyin vivo, however, in markedly different doses. Cyanamide inhibited the high‐KmALDH onlyin vivo, whereasin vitro, the high‐KmALDH was unaffected by cyanamide but significantly inhibited by disulfiram and ACP. The inhibition produced by the inhibitors appeared to be irreversible. Acetaldehyde protected the low‐Kmenzyme at different extents depending on the inhibitor used. The inhibition of ALDH in intoxicated and control rats and its relation to acetaldehyde oxidation and the disulfiram‐ethanol reaction are discussed.
Fluoride, Fluoride Resistance and Glycolysis in Cultured Cells
Authors: Holland Roy I. , Hongslo Jan K.
Published: July 2010

Abstract Long‐term (several years) exposure to fluoride induced decreased production of lactate in cultured, fluoride resistant LS cells. In intact, sensitive cells, 6 mM NaF had no effect on glycolysis, whereas in homogenates, from both resistant and sensitive cells, lactate production was blocked by 6 mM NaF, indicating the cell membrane to be a barrier to fluoride. A lower intracellular rather than extracellular fluoride concentration was found in the sensitive cell with a ratio of 0.4, whereas fluoride resistant cells excluded fluoride from their intracellular milieu.
The Inhibition of Choline Acetyltransferase in Guinea‐pig Cornea
Authors: Fonnum F. , Styr F.
Published: July 2010

Abstract The effects of different compounds on the inhibition of choline acetyltransferase in guinea pig cornea have been studied. N‐hydroxyethyl‐4(naphthylvinyl)pyridinium bromide inhibited the enzyme in the cornea when a 0.5% solution was applied topically to the eye. The inhibition could not be explained by redistribution of the inhibitor after homogenization of the tissue. Inhibition of the enzyme was slowly reversed and nearly full enzyme activity was obtained when the eye was left intact for 48 hrs. N‐methyl‐4(naphthylvinyl)pyridinium bromide was a less efficient inhibitor in vivo and no inhibition was found with bromo acetonyl trimethylammonium bromide or acryloylcholine. Corneal ChAT was inhibited by the application of 3‐methyl‐5‐methoxyphenyl pyridinium bromide, but the mechanism was obscured by the compound causing corneal oedema. The investigation shows that epithelium of the cornea can be used to test the in vivo effect of choline acetyltransferase inhibitors.
Qualitative Alterations of Cytochrome P‐450 in Mouse Liver Microsomes after Administration of Acrylamide and Methylmethacrylate
Authors: Nilsen Odd. G. , Toftgård Rune , Ingelman‐Sundberg Magnus , Gustafsson Jan‐Åke
Published: July 2010

AbstractCytochrome P‐450 in mouse liver microsomes was characterized by SDS‐polyacrylamide gel electrophoresis after intraperitoneal injection of 80 mg phenobarbital, 4.5 and 45 mg acrylamide and 60 and 600 mg methylmethacrylate per kg body weight each day for four days. Four different forms of cytochrome P‐450 with molecular weights of 47,000, 50,000, 54,000 and 56,000 were identified by staining for peroxidase activity and protein. The amount of cytochrome P‐450 with a molecular weight of 47,000 (MLvMc P‐45047) decreased in the phenobarbital group and in both acrylamide groups. After methylmethacrylate treatment, this form increased at the low dose but was totally repressed at the high dose. The cytochrome P‐450 form with a molecular weight of 50,000 (MLvMc P‐45050) was significantly increased only in the phenobarbital group. An increase in the total amount of cytochrome P‐450 was only observed following treatment with phenobarbital.
Autoradiographic Studies of 3H‐estramustine in the Rat Ventral Prostate
Authors: Appelgren L.‐E. , Forsgren B. , Gustafsson J.‐Å. , Pousette Å. , Högberg B.
Published: July 2010

Abstract The alkylating agent 3H‐estramustine was administered to castrated male rats and found to accumulate in the epithelium of the ventral prostate 5 and 20 min. following intravenous administration, as judged from autoradiography. Four hrs. after intravenous injection of this isotope, the radioactivity was recovered in the secretion of the prostatic lobuli. A preferential accumulation of radioactivity in prostatic secretion was also observed 2 hrs. after intramuscular administration of 3H‐estramustine to intact or castrated rats. In contrast, 3H‐oestradiol and 3H‐testosterone, which were also taken up by the ventral prostatic epithelium, were not recovered in prostatic secretion.

The present results indicate that 3H‐estramustine is secreted from the prostatic cells into the lumina of the prostatic lobuli. It is speculated that a recently detected estramustine‐binding protein in rat ventral prostate may be involved in this process and that the present finding may be of relevance in the understanding of the mechanism of action of the chemotherapeutic agent Estracyt® (estramustine phosphate) used in the treatment of advanced prostatic carcinoma.
Pharmacokinetics and Locomotor Activity Increasing Effect of Ephedrine in Mice
Authors: Marvola Martti , Kivirinta Ritva
Published: July 2010

Abstract Ephedrine has stimulating effects on the CNS which have been shown as increased locomotor activity, for example. No studies on the relationship between this pharmacological effect and blood levels of the drug have been reported. In the present study this question was investigated in mice after intravenous and oral administration of ephedrine. It was concluded that after intravenous injection of ephedrine the blood concentration data fitted best with the two‐compartment open model but after oral administration of the drug with the one‐compartment model. The locomotor activity stimulating effect of the drug did not have a linear relationship to the drug levels in the central or in the tissue compartment. This suggests that the mechanism of the locomotor activity increasing effect of ephedrine is indirect.
Beta‐Adrenoceptor Stimulation of the Human Urinary Bladder in Vivo.
Authors: Norlén Lars , Sundin Torsten , Waagstein Finn
Published: July 2010

Abstract The effect of beta‐adrenoceptor stimulation on the volume of the urinary bladder in 16 neurologically normal humans without symptoms of micturition disturbances was investigated. Terbutaline, a selective beta2‐adrenoceptor stimulating agent, was tested in 9 persons and isoprenaline, a general beta‐adrenoceptor stimulating agent, was tested in 7 persons. After terbutaline the maximum increase in the bladder volume was 10% and on an average around 5%. After isoprenaline the maximum increase in the bladder volume was 15% and on an average around 5%. Terbutaline as well as isoprenaline administration resulted in tachycardia and an increased pulse pressure. The tachycardia was somewhat more marked after isoprenaline. In conclusion, only a small increase in the volume of the urinary bladder was noted after beta‐adrenoceptor stimulation in neurologically normal humans without symptoms of micturition disturbances, in contrast to effects achieved in some patients with urgency. Terbutaline seems to have less cardiac effects compared to isoprenaline and is therefore to be preferred when beta‐adrenoceptor stimulation is required in patients with urgency.
Carbon Disulphide Induced Activation of Liver UDP glucuronosyltransferase in Rats Pretreated with Phenobarbitone
Authors: Järvisalo J. , Zitting A. , Vainio H.
Published: July 2010

Abstract Carbon disulphide (CS2) exposure has been shown to activate the UDPglucuronosyltransferase of liver microsomes in rats pretreated with phenobarbitone. Now the nature of CS2 induced activation of the enzymes has been studied further. Phenobarbitone pretreated rats were exposed to 0.15% CS2 for 2 hrs on two successive days. The activity of UDPglucuronosyltransferase was measured from the liver microsomes after the enzymes was activated by incubation of the microsomes with various concentrations of the detergents Triton X‐100, digitonin and cetylpyridinium chloride. The exposed animals showed an increased enzyme activity at all applied concentrations of the detergents; therefore in addition to membrane destruction by CS2 exposure, some other mechanism must also be involved in the CS2 induced activation of liver microsomal UDPglucuronosyltransferase. The changes in membrane lipid‐protein interactions with 1‐anilino‐8‐naphthalene sulphonate (ANS) were also probed. The CS2 exposed animals had more high‐affinity binding sites for ANS in their liver microsomal membranes, and in addition the quantum yield of ANS fluorescence was enhanced by CS2. The changes differed from those found after carbon tetrachloride exposure and suggest that, even if the two drugs have some common effects on microsomes, e.g. UDPglucuronosyltransferase activation, P‐450 destruction and lipid peroxidation induction, the changes they cause in the microsomal micro‐environment differ.
Effect of Trichloroethylene on Cilia Activity in Rabbit Trachea
Authors: Tomenius L. , Holma B. , Ehrner‐Samuel H. , Kylin B. , Tebrock O. , Thomason M.
Published: July 2010

Abstract The ciliotoxicity of trichloroethylene was studied in terms of the time required for ciliostasis in specimens of trachea from 35 male rabbits following exposure of the specimens to different vapour concentrations. The highest vapour concentration was linked with the most rapid ciliostasis but even in the lowest concentration tested, 5.000 p.p.m. (26g/m3), hastened ciliostasis. Specimens from the upper region of the trachea underwent ciliostasis more slowly than did those from the lower region. The absolute uptake of trichloroethylene was lower in the former than in the latter specimen. The difference in uptake could not be explained by a difference in weight or in lipid content. That ciliostasis occurred at different times depending upon the region of the trachea, favours the theory of a critical tissue concentration for trichloroethylene.
Delayed Hypersensitivity to Tuberculin in Rats: Effects of Antirheumatic Drugs
Authors: Bramm E. , Binderup L. , Arrigoni‐Martelli E.
Published: July 2010

Abstract The effects of different antirheumatic drugs administered according to various dosing regimes on tuberculin hypersensitivity in rats have been assessed quantitating the changes of exudate volume and mononuclear cells immigration at the site of challenge. Dosing at the time of sensitization with aurothiomalate and D‐penicillamine enhanced the cell immigration which was decreased by similar treatment with levamisole. Cyclophosphamide increased the exudate formation. Indomethacin had no effect. Dosing at the time of challenge caused a marked reduction of both the parameters by aurothiomalate and cyclophosphamide and enhancement by levamisole. D‐penicillamine increased only the cellular immigration and indomethacin the exudate formation. Long treatment with aurothiomalate and cyclophosphamide suppressed the responses. Similar treatment with D‐penicillamine and levamisole produced a significant enhancement. Indomethacin had no effect. The relevance of these findings to the testing and mode of action of antirheumatic drugs is discussed.
Haemodynamic Effects of the Quaternary Ammonium Compound QX 572 in Anaesthetized Cats. I. Cardiac Chronotropic Effects
Authors: Åberg G. , Kopp U. , Ryén L.
Published: July 2010

Abstract The haemodynamic effects of the antiarrhythmic compound, QX 572, have been studied in anaesthetized cats. It was found that QX 572 increased the heart rate and decreased the blood pressure of the cats during the infusion of the drug. A slight increase in blood pressure was seen after the infusion was terminated. The same results have been obtained in patients. Experiments on cats pretreated with propranolol or reserpine showed that infusions of QX 572 caused an increase in heart rate by increasing the sympathetic activity in the cats. It is also shown that changes in vagal tone may contribute to the effects of QX 572 on the heart rate.
Haemodynamic Effects of the Quaternary Ammonium Compound QX 572 in Anaesthetized Cats. III. Interactions with Adrenergic β‐Adrenoceptor Blockade
Authors: Åberg C. , Arfwidsson I.
Published: July 2010

Abstract The positive cardiac chronotropic effects of the antiarrhythmic compound, QX 572, in anaesthetized cats has been shown mainly to be due to a release of catecholamines from sympathetic nerve‐endings. Furthermore, these undesired effects of QX 572 on heart rate were decreased by adrenergic beta blockade in the animals, In the present study it was found that an adrenergic beta‐blockade did not reveal any cardio‐depressive effects of QX 572, that in the normal animals might have been masked by the effects of the drug‐induced catecholamine‐release.
The Effect of Selenium on the Biliary Excretion and Organ Distribution of Mercury in the Rat after Exposure to Methyl Mercuric Chloride
Authors: Alexander Jan , Norseth Tor
Published: July 2010

Abstract The influence of selenium compounds on the biliary excretion and the organ distribution of mercury after injection of methyl mercuric chloride (4 μmol/kg) have been tested. Selenite, seleno‐di‐N‐acetylglycine and seleno‐methionine strongly inhibited the biliary excretion of mercury. Selenite even in a molar dose of 1/40 of the methyl mercury dose inhibited the biliary excretion of mercury. The less toxic seleno‐di‐N‐acetylglycine was needed in larger molar doses and did not act as rapidly as selenite. Biliary excreted methyl mercury is known to be partly reabsorbed in the gut. Subsequently a part of it is deposited in the kidneys since drainage of the bile lowered the kidney content of mercury. Rats given selenium compounds in combination with bile drainage showed further reduction of the kidney mercury content than bile duct drainage alone. Thus the demonstrated lowering effect of selenium compounds on the kidney mercury content cannot be completely explained by an inhibition of biliary excretion of mercury. The mercury concentration in the brain was increased by the selenium compounds; the effect being dependent of the selenium dose reaching a maximum at an equimolar selenite ‐ to methyl mercury dose ratio. The mechanisms by which selenium influences the methyl mercury kinetics are discussed.
Pharmacokinetics of Femoxetine in Man
Authors: Lund J. , Christensen J. A. , Bechgaard E. , Molander L. , Larsson H.
Published: July 2010

Abstract The pharmacokinetics of a structurally new 5HT‐uptake inhibitor, femoxetine (FG 4963), with antidepressant properties have been investigated in man using a radioactive as well as a non‐labelled substance. A two compartment open model gives a good description of the data, both after oral and intravenous administration. The substance was almost completely absorbed after an oral dose, but only 5‐10% reached the systemic circulation due to extensive first pass metabolism. The metabolites had distribution and excretion rates similar to the parent compound. Only a small part (<2%) was excreted as femoxetine in the urine. The urinary excretion of the parent compound varied more than a 100‐fold depending on the pH of the urine. The urine pH, however, did not influence the plasma concentration of femoxetine. Most of the substance (up to 80%) was eliminated by urinary excretion of metabolites, and only a small part of the radioactive dose was excreted in the faeces (up to 11%). The pharmacokinetic parameters were not found to be dose dependent in the range investigated, but it was not possible to decide whether the bioavailability was dependent on the dose. The variation between subjects was rather large, giving only a limited possibility for prediction of the plasma concentration from one subject to another.
The Distribution of 14C‐Ethoxyquin in Rat
Authors: Skaare Janneche Utne , Nafstad Inger
Published: July 2010

Abstract Adult male rats were given the antioxidant 14C‐ethoxyquin by oral intubation and were sacrificed at various time intervals from 0.5 hr to 6 days following administration of the drug. The distribution pattern was studied by whole‐body autoradiography and liquid scintillation counting. The isotopelabelled antioxidant was distributed throughout most tissues and the blood at 0.5 hr after administration. The highest radioactivity throughout the experimental period was observed in the liver, the kidney, the gastrointestinal tract and the adipose tissue. No activity was observed in the brain and the central nervous system. Of the dose ingested 2.2 and 0.2% were found in the liver at 0.5 hr and 6 days respectively following dosing. The hepatic peak in radioactivity was measured at 8 hrs and after 6 days 7.5% of this level was still present in the liver. Six days after administration residues of ethoxyquin and metabolites were also present in the kidney cortex, the intestines, the lung, various adipose tissue and blood.
The Loss of Creatine Phosphokinase (CK) from Intramuscular Injection Sites in Rabbits. A Predictive Tool for Local Toxicity
Authors: Svendsen Ove , Rasmussen Folke , Nielsen Poul , Steiness Eva
Published: July 2010

Abstract The CK activity was measured in muscle tissue taken from the injected area (dorsal longissimus muscle) and the contralateral side of the injection site 72 hours after intramuscular injection into rabbits of 1 ml of different dilutions of propylene glycol orglycerol formal in distilled water or 0.9% saline. The total loss of CK activity from the injection site was calculated as the difference between the CK concentration in the normal muscle tissue and that of the injection site from the same animal. From the results the arbitrary amount of muscle tissue depleted of CK activity was further calculated and compared with the severity of the gross pathological findings. A large necrotic area at the injection site was present in all samples with more than 1 g of muscle tissue depleted of CK activity. Minor and probably acceptable pathological changes were found in samples with less than 1 g of muscle tissue depleted of CK activity. The local damaging effect of drug preparations for intramuscular use can thus be evaluated from the calculated amount of muscle tissue depleted of CK activity.
Acute Effects of Temazepam and Nitrazepam on Psychomotor Skills and Memory
Authors: Liljequist Raija , Mattila M. J.
Published: July 2010

Abstract Twelve pretrained healthy students ingested temazepam, nitrazepam, and placebo, each double blind at one‐week intervals in randomized order. Reactive and co‐ordinative skills and critical flicker fusion were measured before each drug intake and 1,2,3,6 and 8 hours after it. Short‐term memory and paired association learning were measured at 1, 3 and 8 hours. The psychomotor responses to drugs were modified by a sequence effect (not at zero tests) which effect varied depending on the drug and parameter. In multivariance analysis it was included to reveal drug effects. Nitrazepam 10 mg increased reaction and co‐ordination errors and also impaired learning and memory. Temazepam 10 mg impaired co‐ordinative skills; on a whole it differed from nitrazepam but hardly from placebo. Temazepam 20 mg impaired co‐ordination, and learning and memory. Both temazepam 20 mg and nitrazepam were experienced sedative. All drug effects were clearest during the first 3 hours, nitrazepam also impaired learning at 8 hours. Temazepam 20 mg seems suitable as a hypnotic.
Studies on Acute Tolerance to Ethanol in the Abstinence Period after Long‐term Barbital Treatment in the rat
Authors: Wahlström Göran
Published: July 2010

AbstractMale rats were treated with sodium barbital in the drinking water for 18 weeks. The average weekly dosage was around 215 mg/kg in groups 1, 3 and 5. Groups 2, 4 and 6 were controls. Every week in the abstinence period after the barbital treatment the sensitivity to hexobarbital was tested with a threshold method after three different pretreatments. These pretreatments consisted of saline (groups 1 and 2) and ethanol (2.0 g/kg intraperitoneally) given either 0.25 hr (groups 3 and 4) or 2.5‐3 hrs (group 5 and 6) prior to the hexobarbital test. Tolerance seen as a difference in the sensitivity to hexobarbital between groups 1 and 2 (saline pretreatment) were found on day 1, 8, 22 and 36 in the abstinence period. In groups 3 and 4 (tested 0.25 hr after ethanol) a tolerance was found on day 1 and 15. In groups 5 and 6 (tested 2.5‐3 hrs after ethanol) a tolerance was only found on day 1. An acute tolerance to ethanol in the controls (seen as a difference between groups 4 and 6) was always recorded. Since tolerance in group 1 was not always accompanied by a tolerance in group 3, an acute tolerance to ethanol is unlikely as an unitary explanation to the tolerance induced by the barbital treatment, which instead seem to be part of much more complex changes. The acute tolerance to ethanol was influenced by the weekly administrations of ethanol used in the tests of the controls (groups 4 and 6) which means that acute tolerance could be one participant in these more complex changes.
Storage of Blood Samples Containing Alcohol
Authors: Meyer Trygve , Monge Per Kr. , Sakshaug Johan
Published: July 2010

Abstract The storage of blood alcohol samples was studied. The samples were analysed and then frozen and kept at — 20° for 6 months before reanalysis. The results from this reanalysis did not deviate to any significant extent from those originally obtained. The process of freezing and thawing the same samples before analysis was repeated three times without any significant difference from the results obtained with the fresh blood samples.
Binding of 63Ni by Cellular Constituents in Some Tissues of Mice after the Administration of 63NiCl2 and 63Ni(CO)4
Authors: Oskarsson Agneta , Tjälve Hans
Published: July 2010

Abstract One and 24 hours after the administration of 63NiCl2 and 63Ni(CO)4 to mice 63Ni was present in association with both particulate and soluble cellular constituents in the lung, liver and kidney. After disruption of the cellular organells by sonication, a considerable part of the 63Ni was still bound to the cellular fragments. Sephadex G‐75 chromatography of the cytosol of the lung showed that the largest proportion of 63Ni was eluted in the void volume and a smaller proportion was present in the salt volume. In the kidney, the proportions were reversed. Twentyfour hours after the injection of 63NiCl2 an intermediate 63Ni‐containing peak, with an estimated molecular weight of about 30,000, was found in the lung and the kidney. In the liver of 63NiCl2‐injected mice, most of the nickel was recovered in the void volume, a lesser amount in the salt volume. There was no evidence that 63Ni was bound to metallothionein (induced by Cd‐pretreatment) or to superoxide dismutase in the studied tissues. Pretreatments with non‐labelled NiCl2 did not alter the elution profiles. In serum, most 63Ni was present in association with albumin. Gel‐chromatograms of red blood‐cell hemolysates from 63Ni(CO)4‐injected mice showed 63Ni at an elution volume corresponding to hemoglobin, but 63Ni‐binding ligands with higher and lower molecular weights were also present.
Embryotoxicity and Teratogenicity of Styrene and Styrene Oxide on Chick Embryos Enhanced by Trichloropropylene Oxide
Authors: Kankaanpää J. T. J. , Hemminki K. , Vainio H.
Published: July 2010

AbstractThe effects of TCPO (trichloropropylene oxide) on the embryotoxicity and teratogenicity of styrene and styrene oxide on chick embryos were investigated. The compounds were injected into the air space of the eggs in a total volume of 25 μI on the third day of embryogenesis. TCPO increased embryotoxicity and teratogenicity of styrene and styrene oxide. Our results present evidence that the epoxides possess embryotoxic and teratogenic properties in chick embryos.
Activation of Factor XII in Plasma from Rats Pretreated with Tranexamic Acid. Inhibition of a Plasmin‐induced Loss of the Functional Activity of High Molecular Weight Kininogen
Authors: Briseid Kjell , Ryssdal Anne Berit
Published: July 2010

Abstract: Incubation of plasma from rats pretreated with tranexamic acid (40 mg/l 00 g) with acetone (23 % v/v) yielded enzyme preparations in which all the plasminogen present was recovered as plasmin and a plasmin‐like substance without affinity for lysine‐Sepharose. This substance, designated “plasmin”, was separated from plasmin and kallikrein in a three‐step procedure using columns of lysine‐Sepharose, DEAE‐Sephadex A‐50, and arginine‐Sepharose. The ratios of fibrinolytic, caseinolytic, LEe esterase, BAEe esterase and kininogenase activities of “plasmin” corresponded well with those of rat plasmin and human plasmin. Both rat plasmin and “plasmin” destroyed the capacity of high molecular weight kininogen (HMWK) to function as a cofactor in the activation of factor XII in rat plasma, without causing a corresponding release of the kinin part of the molecule. Rat plasma kallikrein induced full release of kinin from HMWK, but the functional capacity was retained. It is suggested that the reduced extent of activation of factor XII observed in plasma from rats injected intravenously with dextran, or rat plasma that has been passed through a column with lysine‐Sepharose, is due to the loss of functional HMWK caused by plasmin activated in vivo or on the column.
Dextran‐Induced Release of Serotonin from Isolated Rat Peritoneal Mast Cells
Authors: Berstad Jan
Published: July 2010

Abstract: Dextran (9 mg/ml incubate) was found to induce a serotonin (5‐HT) release from isolated rat peritoneal mast cells of about 10% within an incubation period of 5 min. at 37°. The extent of release was not increased by using higher concentrations of dextran or by increasing the incubation period from 5 to 20 min. The dextran‐induced release of 5‐HT was increased to 50–60% when the mast cells were preincubated with phosphatidylserine (PS) in doses of 2.6–4.3 μg/ml incubate. Higher concentrations of PS alone induced a rapid 5‐HT release of approximately 50–60%. The 5‐HT release process studied was found to possess both similarities and dissimilarities with the previously described dextran‐induced release process of histamine, also studied in isolated rat peritoneal mast cells. The results supported previous indirect evidence of a 5‐HT release from mast cells in the early phase of the dextran‐induced anaphylactoid reaction in the rat.