bluuebunny/crossref_metadata_2025 huggingface dataset:
On the Pathogenesis of Cardiac Necroses induced by Theophylline and Caffeine
Authors: Strubelt Otfried , Hoffmann Angela , Siegers Claus–Peter , Sierra–Callejas José–Luis
Published: July 2010

Abstract In unanesthetized rats, theophylline or caffeine in a dose of 150 mg/kg intraperitoneally caused a long–lasting tachycardia, hypermetabolism and hypotension. After 48 hours myocardial necroses were found in all the animals. Propranolol diminished the cardiotoxic as well as the chronotropic, calorigenic and hypotensive effects of theophylline. The calcium antagonists verapamil and D 600 were ineffective in this respect but augmented the acute toxicity of theophylline. Furthermore, the cardiotoxic activity of theophylline was intensified by pretreatment with thyroxine. Total myocardial calcium increased within one hour after the injection of a cardiotoxic dose of isoprenaline (10 mg/kg intraperitoneally) but not after theophylline (150 mg/kg intraperitoneally). Only 24 hours after the theophylline treatment were the myocardial calcium levels elevated. In conclusion, cardiac necroses may be a consequence of hypoxia resulting from the cardiovascular and metabolic actions of theophylline or caffeine. Myocardial calcium overloading does not seem to be an essential factor in the pathogenesis of these necroses.
The Metabolism of Biphenyl. I. Metabolic Disposition of14C–Biphenyl in the Rat
Authors: Meyer Trygve , Aarbakke Jarle , Scheline Ronald R.
Published: July 2010

AbstractThe metabolic disposition of14C–biphenyl in the rat was studied by liquid scintillation counting. The rats were given an oral dose of14C–biphenyl (100 mg/kg, 0.7–1.0 μci) and the total excretion of radioactivity after 96 hrs was 92.2 % of the dose. Urinary excretion accounted for 84.8 % and faecal excretion for 7.3% of the dose. Most of this radioactivity, 75.8 % and 5.8% respectively, was excreted within 24 hrs. Only trace amounts of14CO2were detected in the expired air and 0.6% of the dose was found to be still present in the rats 96 hrs after biphenyl administration. Extraction and fractionation of the 24 hrs urine samples showed that the largest fraction (nearly 30% of the dose) consisted of conjugated phenolic metabolites. Acidic metabolites accounted for a quarter of the dose and the low levels of expired14CO2indicated that these were not products resulting from extensive degradation and decarboxylation.
Different Effects of Microsomal Enzyme Inducers on the Biliary Excretion of Digoxin1
Authors: Nevasaari Kaisu , Alakare Birgitta , Kärki N. T.
Published: July 2010

AbstractThe effects of pretreatment with spironolactone, phenobarbital and 3,4–benzpyrene on biliary excretion of digoxin was studied in the isolated perfused rat liver system after a single dose of3H–digoxin. After spironolactone pretreatment (100 mg/kg intraperitoneally for 4 days) the treated group excreted into bile in 45 min. 67 % of the administered dose compared to about 27 % in the control group. Since there was no significant increase in bile flow at any of the time periods, the enhanced biliary excretion of digoxin was entirely due to the increase in the bile level of digoxin or its metabolites or both. Pretreatment with phenobarbital (75 mg/kg intraperitoneally for 4 days) resulted in a slight increase in bile level of tritium at 15 min. and in bile flow, which could account for the doubled amount of digoxin excreted by the treated group, as compared to the control group at 45 min. Bile flow and biliary excretion of digoxin were unaffected by pretreatment with 3,4–benzpyrene (20 mg/kg intraperitoneally for 4 days). The results suggest that the enhancing effect of spironolactone and phenobarbital on biliary excretion of digoxin is a result of different mechanisms of action, which can not be directly related to the induction of microsomal drug metabolism.
Biliary Excretion of Ouabain in Isolated Perfused Rat Liver after Treatment with Microsomal Enzyme Inducers1
Authors: Nevasaari Kaisu , Alakare Birgitta , Kärki N. T.
Published: July 2010

AbstractThe effects of pretreatment with spironolactone, phenobarbital and 3,4–benzpyrene on biliary excretion of ouabain was studied in isolated perfused rat liver system after a single dose of3H–ouabain. Spironolactone pretreatment (100 mg/kg intraperitoneally for 4 days) changed the time course of the excretion, thus accelerating the transport of ouabain into the bile. Phenobarbital pretreatment (75 mg/kg intraperitoneally for 4 days) enhanced bile flow and increased biliary excretion of ouabain only after 15 min. At longer time periods the increase in bile flow diluted the bile level of ouabain there being no difference in the amounts excreted into the bile between the treated and untreated groups. 3,4–benzpyrene pretreatment (20 mg/kg intraperitoneally for 4 days) was without effect on biliary excretion of ouabain. The results suggest that spironolactone differs from phenobarbital in its enhancing effect on biliary excretion of ouabain, possibly through a specific effect on an unknown hepatic transport mechanism.
Investigations on the Antihypertensive Activity of Timolol and Bendroflumethiazide and the Combination in Dogs and Rats
Authors: Nielsen Chr. Kærgaard , Olsen U. Bang , Rønne I. Ahnfelt , Arrigoni–Martelli E.
Published: July 2010

AbstractThe effects of timolol and bendroflumethiazide, either alone or combined in a fixed ratio of 4:1, on blood pressure, plasma renin activity, and plasma potassium concentration, have been investigated in normotensive and renal hypertensive dogs, and in normotensive and spontaneously hypertensive rats. In addition, the urinary kallikrein excretion has been measured in normotensive and hypertensive rats. When administered to hypertensive dogs and rats, the drug combination significantly reduced the blood pressure. Marginal reductions were observed in normotensive animals or after the administration of the single drugs. The thiazide–induced hypokalemia and hyperreninaemia were almost completely antagonised by the concomitant administration of timolol in both animal species. A highly significant elevation of urinary kallikrein excretion was also observed in rats treated with the drug combination. A less marked increase of kallikrein excretion was noted in the bendroflumethiazide treated rats. The possibility that renal haemodynamic changes, in addition to the inhibition of the increase in plasma renin, play a role in the observed antihypertensive effects is discussed.
Effect oi Pyrazole, 4–Methylpyrazole, 4–Bromopyrazole and 4–Iodopyrazole on Brain Noradrenaline Levels of Mice and Rats
Authors: MacDonald Ewen
Published: July 2010

AbstractFour daily doses of pyrazole (50 mg/kg), caused a reduction in rat brain noradrenaline (NA) of over 20% when determined 24 hrs after the final injection. Neither 4–methylpyrazole (10–50 mg/kg), nor 4–iodopyrazole (10–50 mg/kg) had any effect. In mice treated similarly, pyrazole (50–400 mg/kg) caused a dose–dependent decrease in brain NA. Neither 4–methylpyrazole, 4–bromopyrazole nor 4–iodopyrazole caused any significant change in the levels. However if the brain NA levels were examined 6 hrs after a single dose, then in addition to pyrazole, 4–methylpyrazole showed a dose–dependent ability to lower brain NA. 4–bromopyrazole and 4–iodopyrazole, given acutely, caused a dose–dependent decrease in rectal temperature and exploratory behaviour. 4–methylpyrazole, in high doses (200–400 mg/kg) showed similar properties but they did not correlate with the decrease in brain NA. Pyrazole, after acute treatment, showed little ability to change rectal temperature or exploratory behaviour. It is concluded that the NA–depleting effect of pyrazole is not related to inhibition of alcohol dehydrogenase, since other 4–substituted pyrazoles which are more potent inhibitors of the enzyme have little or no effect on brain NA levels.
Studies on the Metabolism of Orange RN in the Pig
Authors: Larsen J. Chr. , Tarding F.
Published: July 2010

AbstractOrange RN (monosodium salt of l–phenylazo–2–naphthol–6–sulphonic acid) was administered to female pigs either by intraveneous injection or by stomach tube. After intravenous injection of Orange RN, 7.8 mg/kg, the following metabolites were indentified in 24–hour urines: Orange RN (31 %), l–(4–hydroxyphenylazo)–2–naphthol–6–sulphonic acid (3 %), p–aminophenol and o–aminophenol (34 % and 4 % of the theoretical yield, respectively). l–Amino–2–naphthol–6–sulphonic acid was present, but not determined. When the urine collection was extended to 72 hours the excretion of p–aminophenol accounted for the remainder of the phenylazo moiety. The excretion pattern for p–aminophenol suggests that Orange RN is partly excreted in the bile and thereafter undergoes azo reduction in the gut. After administration of Orange RN, 78 mg/kg, by stomach tube the following metabolites were identified in the urine: Total coloured metabolites (Orange RN and l–(4–hydroxyphenylazo)–2–naphthol–6–sulphonic acid) (0.4 % of the theoretical yield), p–aminophenol and o–aminophenol (52 % and 6 % of the theoretical yield, respectively) and aniline (0.3 % of the theoretical yield). 1–Amino–2–naphthol–6–sulphonic acid was present, but not determined.
Michaëlis ‐ Menten Kinetics of Phenazone Elimination in the Perfused Pig Liver
Authors: Andreasen Per Buch , Tønnesen Klaus , Rabøl Allan , Keiding Susanne
Published: July 2010

AbstractThe purpose of the present study was to define the elimination kinetics of phenazone (NFN) in the isolated perfused pig liver. In five experiments phenazone was administered as constant infusion to obtain steady‐state periods over a wide range of concentrations. The elimination of phenazone followed saturation kinetics (concentrations 0.1–12 μmol × 1‐1) and the maximal elimination rate (Vmax) was on average 102 μmol × min.‐1× kg‐1liver and the Michaëlis‐constant (Km) of 2.6 mmol × 1‐1. Estimates of Vmaxand Kmfor the microsomal phenazone hydroxylase activity measured in liver biopsies were found to be considerably lower than in the perfused liver. The hepatic elimination of phenazone during perfusion of pig liver at phenazone concentrations corresponding to human therapeutic doses follows first‐order kinetics.
Effect of Acetylated Derivatives of some Sympathomimetic Amines on the Isolated Auricles and Tracheal Chain of the Guinea‐pig
Authors: Marvola Martti , Piirainen Liisa , Autio Sirpa , Airaksinen Mauno
Published: July 2010

AbstractThe effects of acetylation of sympathomimetic amines, tyramine, amphetamine, ephedrine, phenylephrine, orciprenaline, and salbutamol, and their O‐ and N‐acetyl derivatives and the effects of reserpine or physostigmine pretreatment on the isolated auricles and tracheal chain of guinea‐pigs have been studied. All the parent drugs relaxed the tracheal chain and had a positive inotropic and chronotropic effect on the isolated auricles; only amphetamine, on the contrary, contracted the tracheal chain. O‐acetylation of these sympathomimetic amines generally decreased less chronotropic than inotropic action on the isolated auricles. O‐acetylation of tyramine however: actually increased the positive chronotropic activity of drug. As a rule, O‐acetylation also decreased the beta‐adrenergic effect of these compounds on the tracheal chain, but not so markedly as on the isolated auricles. N‐acetylation generally abolished the adrenergic effects of these sympathomimetic amines on the isolated auricles and decreased those effects on the tracheal preparation. N,O‐triacetylation of salbutamol abolished the stimulating effect of the parent drug on the auricles but increased the relaxant activity on the trachea. Physostigmine antagonized the effects of O‐acetyltyramine and O‐triacetylorciprenaline but not those of tyramine and orciprenaline on the trachea preparation. It is concluded that among the sympathomimetic amines acetylation may be utilized for the development of specific bronchodilators and O‐acetylation for inducing drug latentiation.
Effect of a Low‐protein Diet on Acetaldehyde Metabolism in Rats
Authors: Lindros Kai O. , Pekkanen Leena , Koivula Timo
Published: July 2010

AbstractThe effect of dietary changes on liver alcohol and aldehyde dehydrogenase activities as related to effects on ethanol and acetaldehyde metabolism was investigated. Feeding rats for 8 weeks on diets rich in carbohydrate or fat, but with normal protein content, induced minor changes relative to giving a balanced diet. A low‐protein, high‐carbohydrate diet (5 % and 80 % of calory content, respectively) caused a significant reduction of both alcohol and aldehyde dehydrogenase activities in the liver. The activity of the high‐Kmaldehyde dehydrogenase in the microsomal and soluble fractions appeared to be more reduced than that of the low‐Kmenzyme in the mitochondrial fraction. The tail blood acetaldehyde was significantly higher in rats on the protein deficient diet in spite of their reduced ethanol elimination rates. The results suggest that protein deficiency deranges acetaldehyde metabolism and may thus increase the possible contribution of acetaldehyde to the effects caused by ethanol metabolism.
Effects of the Hexahydroxyhexane Myoinositol on Bone Uptake of Radiocalcium in Rats: Effect of Inositol and Vitamin D2 on Bone Uptake of 45Ca in Rats*
Authors: Angeloff L. G. , Skoryna S. C. , Henderson I. W. D.
Published: July 2010

Abstract The objective of this study was to investigate the effects of inositol and vitamin D2 on bone uptake of 45Ca in rats. The radioactive calcium was administered to young rats by orogastric intubation (2 μci/100 g body weight (b. wt.)) with inositol (20 mg/100 g b. wt.) and/or vitamin D2 (500IU/100g b. wt.) to normal rats. Bone uptake of 45Ca was measured after 24 hours by standard technique. Inositol alone produced a 48 % increase in calcium uptake. It is concluded that inositol significantly increases bone uptake of radioactive calcium (P > 0.005). Simultaneous administration of vitamin D2 decreases the effect of inositol considerably, while vitamin D2 has no significant effect.
Effect of Acetyl Derivatives of some Sympathomimetic Amines on the Blood Pressure of the Rat
Authors: Friström Sinikka , Marvola Martti , Klinge Erik , Halmekoski Jaakko
Published: July 2010

AbstractThe effect of five sympathomimetic amines and some of their acetyl derivatives on the blood pressure of the rat was determined on the left carotid artery. After pretreatment with chlorisondamine (1 mg/kg subcutaneously) the blood pressure rise by sympathomimetic amines and their acetyl derivatives was compared with that of adrenaline. If the potency of adrenaline is specified as 100, the potencies of the other drugs are phenylephrine (metaoxedrinum, NFN) 37, tyramine 1.1, O‐acetyltyramine 0.52, amphetamine 0.50, O‐diacetyl‐phenylephrine 0.25, ephedrine 0.23, O‐acetylephedrine 0.02, N‐acetylphenyl‐ephrine 0.01. The effects of N‐acetyltyramine, N‐acetylephedrine and N‐acetyl‐amphetamine are even weaker. Reserpine 5.0 or 0.05 mg/kg intraperitoneally 24 hours before the experiment increased the blood pressure rise by the directly acting sympathomimetic amines and their acetyl derivatives, but decreased the effects of the indirectly acting drugs. After treatment with phenoxybenzamine (2 mg/kg intraperitoneally), adrenaline exhibited the greatest blood pressure decrease and the effects of the other drugs in descending order: orciprenaline, O‐acetyltyramine, phenylephrine, ephedrine, amphetamine, O‐diacetylphenyl‐ephrine and O‐acetylephedrine. Tyramine did not show any blood pressure decrease. The blood pressure decrease by sympathomimetic amines and by their acetyl derivatives was probably due to β‐receptor stimulation because it was prevented by propranolol. The N‐acetyl derivatives recembled their parent drugs with regard to the immediate onset and short duration of their effects. The O‐acetyl derivatives exhibited slower onset and longer duration of effect than their parent drugs. Physostigmine‐pretreatment diminished the rise in blood pressure by O‐acetyltyramine, but the effect of tyramine remained unchanged.
Guanethidine‐induced Acute Hypersensitivity to Noradrenaline in Anaesthetized Rats
Authors: Nielsen Gunnar Damgård
Published: July 2010

AbstractThe changes in mean arterial blood pressure, heart rate and the respective noradrenaline dose‐response curves after guanethidine sulphate (0.25, 1.25, 5, 20, and 40 mg/kg given intravenously) were studied in chloralose‐urethane anaesthetized adult rats. After transient changes a dose‐dependent maximum fall of the blood pressure was observed 15 minutes after the administration of guanethidine. A fall in heart rate was observed after guanethidine sulphate 0.25 mg/kg, whereas 1.25, 5, 20, and 40 mg/kg initially increased the heart rate followed by a decrease to subnormal levels with minimum values 6–24 hours after guanethidine. Normalization of blood pressure and heart rate occurred within 24 hours and 96 hours, respectively. Maximum dose‐dependent enhancement of changes in blood pressure by noradrenaline 0.5 μg/kg was obtained approximately 15 minutes after guanethidine. Following guanethidine 40 mg/kg the response was increased by a factor 2, and normalization occurred within 96 hours. Fifteen minutes after guanethidine, significant changes in the response of the heart rate to noradrenaline 0.5 μg/kg were obtained with guanethidine 1.25, 5, and 20 mg/kg, whereas fully developed hypersensitivity after 20 and 40 mg/kg did not occur until 6–24 hours later. Following guanethidine 40 mg/kg the response was increased by a factor of 3, and normalization was observed after 96 hours. The present investigation has demonstrated different time‐dependent patterns of the effect of guanethidine on blood pressure and heart rate responses to noradrenaline.
Determination of Dextropropoxyphene and Norpropoxyphene in Autopsy Material
Authors: Christensen Hanne
Published: July 2010

AbstractA method for the simultaneous determination of dextropropoxyphene (DP) and its major metabolite norpropoxyphene (NP) in autopsy material, has been developed. By the extraction procedure used, NP is completely converted to its more stable amide form, which like DP, produces well‐defined peaks, in the subsequent gas‐liquid chromatographic determination. Thin‐layer chromatography is used for additional identification of the two compounds. In 20 g of autopsy material, the detection limit is 0.3 μg/g of tissue or body fluid. The recovery of standards added to control blood samples (1.25 μg/g) was 65 ± 10 % (S. D.) for DP and 59 ± 9 % (S. D.) for NP (n = 54). The method is routinely used for determinations in blood, muscle, liver and urine.
Biochemical Effects of Baclofen (β‐Parachlorophenyl‐GABA) on the Dopamine and the Noradrenaline in the Rat Brain
Authors: Andén Nils‐Erik , Wachtel Helmut
Published: July 2010

AbstractBaclofen (fi‐parachlorophenyl‐GABA) caused an increase in the concentration of dopamine in the rat brain with a maximum of about 170%of the control value after 1 hr and after doses of 50 mg/kg or more intraperitoneally. The α‐methyltyrosine‐induced disappearance of dopamine was inhibited to about the same extent in the corpus striatum and in the limbic system by baclofen. The accumulation of DOPA following decarboxylase inhibition was stimulated more in the corpus striatum than in the limbic system by baclofen, thus accounting for the fact that the concentration of dopamine was elevated about three times as much in the corpus striatum as in the limbic system. Amphetamine almost completely inhibited the rise in dopamine produced by baclofen. Baclofen did not cause any consistent changes in the concentration, the synthesis and the utilization of noradrenaline. These effects of baclofen are similar to those described following gammahydroxybutyric acid or axotomy. Hence, baclofen might also interrupt the nerve impulse flow in central dopamine neurones, perhaps by stimulating a central GABA mechanism.
Thein VivoToxicity of CS2to Liver Microsomes: Binding of Labelled CS2and Changes of the Microsomal Enzyme Activities
Authors: Järvisalo J. , Savolainen H. , Elovaara E. , Vainio H.
Published: July 2010

AbstractThe binding of35S and14C labelled CS2to liver microsomes was studied in control and phenobarbitone pretreated rats 3 and 6 hrs after an intraperitoneal injection. The level of hepatic cytochrome P‐450, the activities of epoxide hydratase and UDP‐glucuronosyltransferase were analyzed in the same animals. The binding of the sulphur label was considerably higher than that of carbon 3 hrs after the injection, the difference being less evident at 6 hrs. The measurable P‐450 declined after the CS2injection. It was approximately 40 % in the phenobarbitone pretreated rats and 60 % in control rats of the values of animals which were not treated with CS2. CS2did not affect microsomal epoxide hydratase activity, while it increased the measurable activity of UDP‐glucuronosyltransferase. The increase was evident 3 hrs after the injection of CS, in the phenobarbitone pretreated rats. It could also be detected in the control animals 6 hrs after the injection. The present data suggest that the change in the measurable P‐450 results from the binding of the metabolite(s) of CS2to the cytochrome, and its subsequent degradation. The increase in measurable UDP‐glucuronosyltransferase activity results probably from the activated perturbation of the structure of microsomal membrane by the metabolites of CS2in vivo.
Effects of Cholinergic Drugs and Imidazole on Ca Release and Cyclic AMP Formation in Microsomal Fractions from Rabbit Colon
Authors: Nilsson Karin B. , Andersson Rolf G. G.
Published: July 2010

AbstractFollowing the addition of carbachol or acetylcholine to microsomal fractions isolated from rabbit colon which were preloaded with Ca, the ions were rapidly released. In the 35‐45% fraction Ca was completely released within 10 min., but in the 35 % fraction only 30 % was released. Carbachol reduced the adenylate cyclase activity of the 35‐45 % fraction. Both these effects were blocked by atropine. Exogenous cyclic AMP completely inhibited the Ca‐releasing action of carbachol in the 35 % fraction and markedly reduced it in the 35‐45 % fraction. Imidazole released Ca from the 35‐45 % fraction and stimulated its phosphodiesterase activity. It is suggested that the microsomal fractions are parts of a Ca‐sequestering system in smooth muscle which are able to bind Ca and which on the addition of some contracting drugs release the ions and thereby activate the contractile system. The release of Ca may partly at least be due to a reduction of the adenylate cyclase activity, although other mechanisms must also be considered.
Effects on Rat Liver Acetaldehyde Dehydrogenasesin Vitroandin Vivoby Coprine, the Disulfiram‐like Constituent of Coprinus atramentarius
Authors: Tottmar O. , Lindberg P.
Published: July 2010

AbstractCoprine, the disulfiram‐like constituent of the mushroom Coprinus atramentarius was found to inhibit the low‐Kmacetaldehyde dehydrogenase in rat liver and to increase the acetaldehyde level in blood during ethanol metabolismin vivo.Coprine did not inhibit the low‐Kmenzymein vitro, but the hydrolytic product of coprine, 1 ‐aminocyclo‐propanol, was a potent inhibitor bothin vitroandin vivo.A rapid onset of inhibition was observed after administration of coprine and the inhibition was long‐lasting. It is suggested that 1‐aminocyclo‐propanol is responsible for the inhibition caused by coprinein vivo.
The Renal Handling of Lithium: Relation Between Lithium Clearance, Sodium Clearance and Urine Flow in Rats with Diabetes Insipidus
Authors: Thomson Klaus
Published: July 2010

AbstractIn order to study the renal handling of lithium, I examined the relation between the lithium clearance and the urine flow in rats which had hereditary lack of vasopressin production and which had been given a test dose of lithium. The two variables were altered by varying the sodium intake. Rats with a low, medium and high sodium intake had a mean lithium clearance of 0.04, 0.22, and 0.40 ml/min./100 g body weight, respectively. When the sodium intake was increased from a medium to a high level, the lithium clearance and the urine flow rose in proportion to each other (r = 0.90). When the sodium intake was decreased from a medium to a low level, the lithium clearance fell relatively more than the urine flow so that the proportion between the two was changed. The experiments show that when vasopressin‐induced alterations of the urine flow are excluded and when the sodium intake is not extremely low, proportionality may occur between the lithium clearance and the urine flow. This suggests that the lithium clearance varies in proportion to and is determined by the delivery of sodium from the proximal tubules.
Inotropic Action and Myocardial Uptake of Digoxin and Betamethyldigoxin in Isolated Guinea Pig Atria
Authors: Allonen Hannu , Iisalo Esko , Kanto Jussi , Pihlajamäki Kalevi
Published: July 2010

AbstractThe chronotropic and inotropic effects as well as the tissue levels of digoxin and methyldigoxin were studied in isolated guinea pig atria. Higher concentrations of methyldigoxin than of digoxin were required to cause arrhythmias. The inotropic potencies of the two glycosides did not differ from each another in equimolar concentrations in the organ bath. The increase in contractility correlated with the level of the glycoside in the organ bath and in the tissue. Digoxin was more effectively taken up by the heart tissue than methyldigoxin. Thus, when the tissue levels of the glycosides were the same, the contractility was greater after methyldigoxin than after digoxin.
Chronic Copper Poisoning in Sheep. III. The Distribution of Soluble Copper‐ and Zinc‐binding Liver Proteins of Lambs compared with Adult Sheep
Authors: Søli Nils E. , Frøslie Arne , Norheim Gunnar
Published: July 2010

Abstract The distribution of copper and zinc among soluble hepatic proteins in lambs from 1 normal and 1 copper dosed ewe was studied by gel filtration. It was found that the distribution pattern is similar in newborn lambs and their dams. The amount of copper in the liver indicated that a placental transfer and accumulation of copper is possible in lambs.
Cyclic AMP and Ca‐binding in Microsomal Fractions Isolated from Rabbit Colon Smooth Muscle
Authors: Nilsson Karin B. , Andersson Rolf G. G. , Mohme‐Lundholm Ella , Lundholm Lennart
Published: July 2010

AbstractFrom a homogenate of rabbit colon muscle two ATP dependent Ca‐accumulating microsomal fractions were isolated by differential centrifugation on a sucrose density gradient at 35 % and 35‐45 % sucrose. Adenylate cyclase and phosphodiesterase activities were found in the fractions. The Ca‐accumulation and the ATPase activity of these fractions were stimulated by cyclic AMP (10‐5M) at an ATP concentration of 0.35 mM ATP. In the presence of higher concentrations of ATP (5 mM) cyclic AMP had no effect on the Ca‐binding. The higher concentration of ATP markedly increased the cyclic AMP formation in relation to the activity found at the lower concentration of ATP. Isoprenaline (2 × 10‐6M) stimulated the Ca‐accumulation in the 35‐45 % fraction and increased the hydrolysis of ATP. These effects were absent in the fraction isolated at 35 % sucrose. In the former fraction isoprenaline also stimulated the adenylate cyclase activity at 0.35 mM but not at 5 mM ATP. Both the effect of isoprenaline on the Ca‐binding and the adenylate cyclase activity were inhibited by the adrenergic β‐receptor blocking agent sotalol. In the 35‐45 % fraction papaverine (1 × 10‐3M) stimulated the Ca‐accumulation and inhibited the phosphodiesterase activity. It is suggested that cyclic AMP and agents which influence the cyclic AMP metabolism in the microsomes may have a regulatory role on the Ca‐binding of the microsomes.
Plasma Nitrazepam Concentrations after an Acute Intake and their Correlation to Sedation and Serum Growth Hormone Levels
Authors: Kangas L. , Kanto J. , Syvälahti E.
Published: July 2010

Abstract Concentrations of nitrazepam in plasma were determined by gas chromatography in healthy volunteers after an acute peroral administration of nitrazepam (5 and 10 mg). Placebo tablets were also used, and an assessement of subjective drug effects was made during each medication. In addition serum growth hormone levels were determined. The peak plasma nitrazepam concentration was achieved at 120 minutes (46.9 ± 3.2 ng/ml, mean ± S.E.M.) after 5 mg of nitrazepam and at 180 minutes (82.8 ± 10.5 ng/ml) after the dose of 10 mg. The half‐life of nitrazepam in plasma ranged from 16.5 to 48.3 (mean 28.8) hours. A significant positive correlation was seen between the subjective sedative effects and the magnitude of the peak nitrazepam concentrations in plasma. This drug effect was highly significant when the plasma levels of nitrazepam were rising. The subjective sedative effects were more prominent after 10 mg than after 5 mg dose of nitrazepam. The plasma nitrazepam concentration was not significantly correlated with the subjective sedative effect the next morning, 12 hours after the drug intake. Serum growth hormone levels rose significantly during the study both after 5 mg and 10 mg nitrazepam doses (peak levels 16.3 ± 4.0 and 12.7 ± 3.1 ng/ml) and were significantly higher than after placebo administration (3.7 ± 0.7 ng/ml).
Cytochrome P‐450‐product Complexes Produced by Amphetamine Derivatives: A Comparative Study with Isolated Liver Microsomes and Hepatocytes
Authors: Hirata Masaharu , Högberg Johan , Thor Hjördis , Orrenius Sten
Published: July 2010

Abstract1. Incubation of liver microsomes from phenobarbital‐treated rats with N‐hydroxyamphetamine or norbenzphetamine in the presence of NADPH and molecular oxygen gave rise to the formation of a cytochrome P‐450‐product complex characterized by maximal light absorption at 456 nm. Complex formation was more rapid and extensive with N‐hydroxyamphetamine than with norbenzphetamine as substrate.

2. When incubation was performed with hepatocytes isolated from phenobarbital‐treated rats, the formation of the cytochrome P‐450‐product complex was less rapid as well as less extensive. In fact, with some cell preparations incubation with norbenzphetamine failed to produce any spectrophoto metrically observable cytochrome P‐450‐product complex.

3. Incubation of the hepatocytes with norbenzphetamine caused a decrease in the cellular level of reduced glutathione (GSH) suggesting consumption of GSH during the metabolism of the drug. Moreover, GSH and certain other sulfhydryl compounds inhibited norbenzphetamine‐induced cytochrome P‐450‐product complex formation in the liver microsomal fraction. The extent of inhibition by GSH was moderately enhanced by the addition to the microsomes of a purified preparation of glutathione‐S‐epoxide transferase.

4. When higher concentrations of norbenzphetamine (> 1 mM), or certain other lipophilic amines, were added to suspensions of hepatocytes, there was a rapid lysis of the cells which was preceeded by a dramatic decrease in the cellular ATP level. This effect could be correlated to uncoupling of phosphorylation from respiration in experiments on isolated rat liver mitochondria.

5. It is suggested that further metabolism via a GSH‐linked pathway may act by decreasing the concentration of cytochrome P‐450‐binding norbenzphetamine metabolite(s) in the hepatocyte, thus inhibiting cytochrome P‐450‐product complex formation from this drugin vivo.
Release of Platelet 5‐Hydroxytryptamine by Some Anorexic and Other Sympathomimetics and their Acetyl Derivatives
Authors: Friström Sinikka , Airaksinen Mauno M. , Halmekoski Jaakko
Published: July 2010

AbstractThe effect on 5‐hydroxytryptamine release from rabbit platelets to plasma of ten known sympathomimetic or anorectic phenethylamines and eight N‐ or O‐acetyl derivatives of these substances were studied in order to find possible structure‐action relationships and a possible correlation to the pulmonary hypertension inducing ability of some anorexigens. Among the mainly indirectly acting sympathomimetics amphetamine and ephedrine showed a similar high 5HT‐releasing effect. Tyramine was slightly weaker, while the direct acting phenylephrine (metaoxedrine) and orciprenaline were much weaker. Acetylation increased the 5HT releasing effect of amphetamine, ephedrine and tyramine but decreased this effect of phenylephrine and orciprenaline. Among the anorectic phenethylamines the 5HT‐releasing effect decreased in the following order, aminorex, amphetamine, clophorex, chlorphentermine, diethylpropion (amphe‐pramon), phentermine. With regard to aminorex, which is a releaser of platelet 5HT and an inhibitor of both MAO activity and 5HT uptake in pulmonary tissue, it seems possible that the pulmonary hypertension can be caused by high concentration of free 5HT.
Metabolism of14C‐Antipyrine in Suspensions of Isolated Rat Liver Cells
Authors: Aarbakke Jarle , Bessesen Atle , Marland Jarg
Published: July 2010

AbstractSuspensions of liver cells isolated from perfused rat livers were incubated with antipyrine‐N‐methyl‐14C. Antipyrine was eliminated by first‐order kinetics during incubations for 3 hours with primary suspensions (parenchymal cells + non‐parenchymal cells) and suspensions of purified parenchymal cells. Antipyrine concentrations were unchanged when incubated with suspensions of non‐parenchymal cells, dead cells or medium only. At the end of incubation period, 4‐OH‐antipyrine and 3‐CH2OH‐antipyrine were detected mainly as the glucuronide or sulphate conjugates, and evidence for the N‐demethylation of antipyrine was also obtained. Half‐lives for elimination of antipyrine in primary cell suspensions were not significantly different from the half‐lives measured in parenchymal cell suspensions. This finding together with the lack of metabolism of antipyrine found in non‐parenchymal cell suspensions suggest that oxidation and conjugation of antipyrine is mainly confined to the parenchymal cells. There was significant inhibition of antipyrine metabolism in primary suspensions by phenylbutazone (1.6 × 10‐3M), dexamethasone (2 × 10‐4M) and ethanol (1.3 × 10‐2M, 0.75 %0). We suggest that the use of primary suspensions of isolated rat liver cells provide a rapid and simple method for the study of factors influencing drug metabolism in the liver.
Simultaneous Determination of Furosemide and Two of Its Possible Metabolites in Biological Fluids
Authors: Mikkelsen E. , Andreasen F.
Published: July 2010

AbstractBy the means of thin‐layer chromatography (TLC) prior to fluorometry it was possible to determine furosemide (F) in plasma and urine with improved specificity. Antranilic acid (A) and 4‐chlor‐5‐sulphamoyl‐antranilic acid (CSA) could be determined simultaneously with F in plasma. In urine, only F and A could be determined quantitatively by this method. The sensitivity is 0.1 μg/ml for F and 0.15‐0.20 μg/ml for A and CSA. By means of TLC prior to fluorometry the blank value for F was reduced in normal subjects and in different groups of patients, and its diurnal variation was eliminated. The average values of the plasma concentrations of F after the intravenous injection of 40 mg into 12 normal subjects were at all times found to be lower by the TLC method than by the fluorometric method without TLC. A higher plasma clearance and a lower volume of distribution were found for F when the values obtained by the TLC method were used for the calculation.
The Pharmacokinetics of Carbamazepine in Plasma and Saliva of Man
Authors: Pynnönen S.
Published: July 2010

Abstract The excretion of carbamazepine in the saliva of six normal adults after receiving a single oral dose of 400 mg carbamazepine is described. There was a good correlation between carbamazepine concentrations in the plasma and saliva (r = 0.94, P < 0.001). This indicates that the concentrations of carbamazepine in the saliva can be used to monitor carbamazepine therapy. The half‐life of carbamazepine in the plasma was not significantly different from the half‐life in the saliva. Thus areas under concentration‐time curves, apparent volumes of distribution (Vd) and the total body clearances were significantly dependent (P < 0.001) upon the distribution of carbamazepine between plasma and saliva. Calculated from saliva concentrations, 75 % of the total carbamazepine plasma concentration is bound to protein while 25 % is unbound in diffusional equilibrium with saliva. These figures are consistent with data in the literature.
Pharmacokinetics of Trimethoprim (TMP) in Normal and Febrile Rabbits
Authors: Ladefoged Ole
Published: July 2010

AbstractThe pharmacokinetics of trimethoprim (TMP) were investigated in normal and febrile rabbits. The half‐life of TMP in rabbits is about 40 minutes and no differences were found between the half‐life in normal and febrile rabbits. A significantly greater volume of distribution of TMP, however, was found in the febrile rabbits. Analysis according to the two‐compartment model showed that the differences are due to a change in the distribution of TMP towards the peripheral compartments.
The Interaction between Physostigmine and Hexobarbital in Male Rats
Authors: Wahlstrom Goran
Published: July 2010

AbstractThe sensitivity to hexobarbital was tested with an EEG‐threshold. Hexobarbital was infused continuously in a tail vein of male rats and the dose needed to obtain a burst suppression of 1 sec. or more in the EEG (the “silent second”) was determined. In the first part of the experiments the dose response and time response of the effect of physostigmine on the hexobarbital threshold was determined. The rats were pretreated with methylatropine 2.0 mg/kg subcutaneously. Testing of three different doses of physostigmine (0.5, 1.0 and 2.0 mg/kg intraperitoneally) showed that only the highest dose raised the hexobarbital threshold. The optimal time interval between the dose of physostigmine and hexobarbital threshold to obtain this effect was found to be around 1.5 hours. In the second part of the experiment the antagonistic effect of atropine was investigated. Methylatropine (2 mg/kg intraperitoneally) combined with physostigmine (2.0 mg/kg intraperitoneally) increased the hexobarbital threshold to 117 ± 4 per cent of a pre‐experimental value. Substitution of methylatropine with atropine (8 mg/kg intraperitoneally) gave a threshold value of 94 ± 4 per cent. Atropine combined with saline gave a threshold of 85 ± 2 per cent. The corresponding value after methylatropine was 100 ± 5 per cent. Thus pretreatment with atropine can reduce the increase in dose of hexobarbital caused by the CNS‐ effects of physostigmine.
Morphological Lesions in Guinea Pigs during Skin Exposure to 1,1,2‐trichloroethane
Authors: Kronevi T. , Wahlberg J. , Holmberg B.
Published: July 2010

AbstractGuinea pigs were exposed to 1,1,2‐trichloroethane applied directly on the skin of the back for periods between 15 minutes and twelve hours under anaesthesia. Morphological changes could be observed in the epidermis after 15 minutes and continued to progress during continuing exposure. The changes consisted of pyknotic nuclei, perinuclear oedema of basal and suprabasilar cells as well as a focal separation of the epidermis from the corium with vesicle formations. The liver tissue showed reduction of glycogen content as well as hydropic changes in the centrilobular areas six hours after the start of exposure. The liver changes were less marked 12 hours after exposure and absent in non‐anaesthetized animals. No morphological changes were observed in the kidney or the brain.
Substituted Amphetamine Derivatives. I. Effect on Uptake and Release of Biogenic Monoamines and on Monoamine Oxidase in the Mouse Brain
Authors: Ross Svante B. , Ögren Sven‐Ove , Renyi Anna L.
Published: July 2010

AbstractThe effects of amphetamine (A), 2‐, 3‐ and 4‐chloroamphetamine (CA), 4‐methylamphetamine (MA) and chlorphentermine (CP) in inhibiting the accumulation and in evoking release of radioactive labelled noradrenaline (NA), dopamine (DA) and 5‐hydroxytryptamine (5‐HT) and in inhibiting the oxidative deamination of tyramine and 5‐HT in mouse brain slices (midbrain and striatum) were examined. The inhibitory potencies on the NA uptakein vitroand after intraperitoneal administration varied only slightly, 3‐CA being the most potent and 2‐CA the least active compound. The structure activity for inhibition of the DA uptake in striatal slices was similar with the exception that CP was the least potent agent. The accumulation of 5‐HT was most potently inhibited by the 4‐ and 3‐substituted amphetamines. Only a small (20 %) fraction of the3H‐NA accumulated in the midbrain slices could be released by the amphetamines but a significant release was obtained at rather low concentrations (5 × 10‐7M). The release of radioactive DA and 5‐HT from striatal slices was much more pronounced and the orders of activities were similar to those for the inhibition of the accumulation of DA and 5‐HT, except that CP was comparatively less active in releasing 5‐HT. The oxidative deamination of tyramine and 5‐HT was most potently inhibited by 4‐CA and 4‐MA and this effect was obtained at the same doses producing inhibition of the amine uptake. No effect was obtained on the deamination of phenethylamine.
The Pharmacology of a New Potent, Long Acting Neuroleptic, Piflutixol
Authors: Nielsen I. Møller , Boeck V. , Christensen A. V. , Danncskiold‐Samsøe P. , Hyttel J. , Langeland J. , Pedersen V. , Svendsen O.
Published: July 2010

AbstractPiflutixol, 6‐fluoro‐9‐[3‐(4‐(2‐hydroxyethyl)piperidino)propylidene]‐2‐trifluoromethyl‐thioxanthene, has been shown to have pronounced neuroleptic properties. It is a very potent inhibitor of methylphenidate‐induced stereotypies in mice, amphetamine‐ and apomorphine‐induced stereotypies in rats, apomorphine‐induced stereotypies and vomiting in dogs. Furthermore piflutixol causes cataleptic reaction in small doses and inhibits conditioned avoidance reaction in rats. The compound is equally potent orally and parenterally and has a prolonged effect. Piflutixol has up to the present proved to be the most potent inhibitor of dopamine‐stimulated adenylate cyclase in rat striatum in vitro. Piflutixol has a strong sedative effect (inhibition of spontaneous motor activity, induction of ptosis and potentiation of barbiturate anaesthesia) and in addition inhibits reticular arousal reaction in very low doses. Thus piflutixol constitutes a unique combination of potent anti‐stereotyped activity with potent sedative effects. This means that piflutixol may prove to be a low‐dose basic neuroleptic with long duration of action.
Effects of Cholinergic Drugs and Imidazole on Ca Release and Cyclic AMP Formation in Microsomal Fractions from Rabbit Colon
Authors: Nilsson Karin B. , Andersson Rolf G. G.
Published: July 2010

Abstract:Following the addition of carbachol or acetylcholine to microsomal fractions isolated from rabbit colon which were preloaded with Ca, the ions were rapidly released. In the 35‐45 % fraction Ca was completely released within 10 min., but in the 35 % fraction only 30 % was released. Carbachol reduced the adenylate cyclase activity of the 35–45 % fraction. Both these effects were blocked by atropine. Exogenous cyclic AMP completely inhibited the Ca releasing action of carbachol in the 35 % fraction and markedly reduced it in the 35–45 % fraction. Imidazole released Ca from the 35–45 % fraction and stimulated its phosphodiesterase activity. It is suggested that the microsomal fractions are parts of a Ca‐sequestering system in smooth muscle which are able to bind Ca and which on the addition of some contracting drugs release the ions and thereby activate the contractile system. The release of Ca may partly at least be due to a reduction of the adenylate cyclase activity, although other mechanisms must also be considered.
Inhibition of Apomorphine‐induced Hypermotility in Rats by Chlorpromazinc, Perphenazine, Thioridazine and Melperone
Authors: Lassen Jørgen Buus
Published: July 2010

Abstract:Hypermotility in rats produced by various subcutaneous doses of apomorphine (ap) was studied. The neuroleptics chlorpromazine, perphenazine, thioridazine and melperone were administered subcutaneously 30 minutes before ap. The four neuroleptics were found to inhibit ap‐induced hypermotility. When the dose of ap was increased, higher doses of the neuroleptics were required to inhibit the hypermotility. By varying the dose of chlorpromazine, thioridazine and melperone partial ap‐antagonism was found, but increase of the perphen‐azine‐dose resulted in complete ap‐inhibition. Hypermotility produced by ap is presumably dependent on direct stimulation of dopamine (DA)‐receptors. Neuroleptics blocking some, but not all, DA‐receptors may cause no, or weak parkinsonian side effects.
Effects on Rat Liver Acetaldehyde Dehydrogenasesin Vitroandin Vivoby Coprine, the Disulfiram‐like Constituent of Coprinus atramentarius
Authors: Tottmar O. , Lindberg P.
Published: July 2010

Abstract:Coprine, the disulfiram‐like constituent of the mushroom Coprinus atramentarius was found to inhibit the low‐Kmacetaldehyde dehydrogenase in rat liver and to increase the acetaldehyde level in blood during ethanol metabolismin vivo. Coprine did not inhibit the low‐Kmenzymein vitro, but the hydrolytic product of coprine, 1‐aminocyclo‐propanol, was a potent inhibitor bothin vitroandin vivo. A rapid onset of inhibition was observed after administration of coprine and the inhibition was long‐lasting. It is suggested that 1‐aminocyclopropanol is responsible for the inhibition caused by coprinein vivo.
The Renal Handling of Lithium: Relation Between Lithium Clearance, Sodium Clearance and Urine Flow in Rats with Diabetes Insipidus
Authors: Thomson Klaus
Published: July 2010

Abstract:In order to study the renal handling of lithium, I examined the relation between the lithium clearance and the urine flow in rats which had hereditary lack of vasopressin production and which had been given a test dose of lithium. The two variables were altered by varying the sodium intake. Rats with a low, medium and high sodium intake had a mean lithium clearance of 0.04, 0.22, and 0.40 ml/min./100 g body weight, respectively. When the sodium intake was increased from a medium to a high level, the lithium clearance and the urine flow rose in proportion to each other (r = 0.90). When the sodium intake was decreased from a medium to a low level, the lithium clearance fell relatively more than the urine flow so that the proportion between the two was changed. The experiments show that when vasopressin‐induced alterations of the urine flow are excluded and when the sodium intake is not extremely low, proportionality may occur between the lithium clearance and the urine flow. This suggests that the lithium clearance varies in proportion to and is determined by the delivery of sodium from the proximal tubules.
Effect of Manganese on Neonatal Rat: Manganese Concentration and Enzymatic Alterations in Brain
Authors: Seth Prahlad K. , Husain Raushan , Mushtaq Mohammad , Chandra Satya V.
Published: July 2010

Abstract: Suckling rats were exposed for 15 and 30 days to manganese through the milk of nursing dams receiving 15 mg MnCl24H20/kg/day orally and after which the neurological manifestations of metal poisoning were studied. No significant differences in the growth rate, developmental landmarks and walking movements were observed between the control and manganese‐exposed pups. The metal concentration was significantly increased in the brain of manganese‐fed pups at 15 days and exhibited a further three‐fold increase over the control, at 30 days. The accumulation of the metal in the brain of manganese‐exposed nursing dams was comparatively much less. A significant decrease in succinic dehydrogenase, adenosine triphosphatase, adenosine deaminase, acetylcholine esterase and an increase in monoamine oxidase activity was observed in the brain of experimental pups and dams. The results suggest that the developing brain may also be susceptible to manganese.