bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolism of metoprolol‐(3H) in man, the dog and the rat
Authors: Borg Karl Olof , Carlsson Enar , Hoffmann Kurt‐Jürgen , Jönsson Tor‐Erik , Thorin Hans , Wallin Boel
Published: July 2010

Abstract:The main urinary metabolites of metoprolol‐(3H) in man, the dog and the rat were identified by gas chromatography and mass spectrometry by comparison with synthesized reference compounds. The amounts of the different metabolites in urine were determined by radio‐gas chromatography. In man metoprolol was metabolized by oxidative deamination, O‐dealkylation with subsequent oxidation and aliphatic hydroxylation into three main urinary metabolites which together accounted for 85% of the total urinary excretion. In the dog and the rat the same metabolites could be recovered but in different relative abundances.

The inhibition of cardiovascular effects of isoprenaline by the metabolites and a presumed metabolite was studied and compared with the effects of metoprolol. Two of the compounds blocked the isoprenaline responses but they were 2–8 times less potent than metoprolol. The metabolites showed a significantly lower acute toxicity in mice than metoprolol.
The Effect of Ethanol on the Duration of Toxic Action of Lidocaine: An Experimental Study on Rats and Mice
Authors: Vuorinen Ilona , Heinonen J. , Rosenberg P.
Published: July 2010

AbstractThe purpose of this study was to determine whether previous acute or subchronic administration of ethanol would alter the toxicity of lidocaine in experimental animals. The principal method used was the measurement of the duration of the narcosis‐like state produced by lidocaine (intraperitoneally) in rats. The concentration of ethanol in the blood of rats was at a maximum about one hour after the administration by gastric intubation. Ethanol in doses of 1.5–3 g/kg, given 1–3 hours previously, caused a significant prolongation of lidocaine narcosis. This prolongation was not due to hypothermia, which occurred in animals at ordinary room temperature. The lethal action of intravenously injected lidocaine in mice was not changed by acute ethanol administration. Lidocaine narcosis was shortened by subchronic ethanol administration but this shortening was statistically significant only when ethanol was given continuously to rats in their drinking fluid. Hence it remains to be shown, for instance, what role the inhibition or induction of drug‐metabolizing enzymes by ethanol plays in the prolongation or shortening of lidocaine narcosis.
Two Compartment Analysis of Plasma Elimination of Phenazone in Normals and in Patients with Cirrhosis of the Liver
Authors: Greisen Gorm , Andreasen Per Buch
Published: July 2010

AbstractThe elimination kinetics of phenazone (NFN) after intravenous injection was investigated in seven healthy volunteers and in five patients with chronic liver disease. The plasma concentration/time data of phenazone were analysed according to a one compartment linear model and a two compartment linear open model, respectively. The elimination rate constant, the volume of distribution, and the clearance estimated by the one compartment model analysis correlated significantly with the corresponding parameters of the two compartment model analysis (r = +0.892, r = +0.989 and r = +0.999, respectively). The initial disposition constant (α) and the rates of distribution of phenazone between the central and peripheral compartment, k12and k21were unaltered in the patients with liver disease, whereas the clearance was significantly reduced. These results confirm that the plasma clearance of phenazone is reliably investigated by sampling only from the terminal phase of the plasma elimination curve.
The Interaction between Hexobarbital and Atropine or Methylatropine in Male Rats
Authors: Wahlström Göran
Published: July 2010

AbstractThe interaction of atropine or methylatropine with a barbiturate was studied in male rats. Different doses of the cholinergic blocking agents were given prior to an anaesthesia threshold determination with hexobarbital. The dose of hexobarbital needed to induce a burst suppression in the EEG which was 1 second or longer (the “silent second”) was used as the threshold. The ensuing anaesthesia times were also measured. Methylatropine in doses up to 8 mg/kg had no discernable effect on the threshold within 5 hrs after the dose. Atropine decreased the threshold 1.5 hr after the administration. The maximal effect was obtained with the largest dose given (8 mg/kg, fig. 2). Both cholinergic blocking agents decreased the body temperature. No measurable effects were obtained on the ensuing anaesthesia times. The synergistic effect found between atropine and hexobarbital in the present experiments is probably brought about through actions in the central nervous system.
Non‐linear Multicompartment Model for Drug Binding by Extracellular Proteins with an Application to Warfarin
Authors: Julkunen R. J. K. , Kekki M. , Himberg J.‐J. , Wahlström B.
Published: July 2010

AbstractFormulae are presented for multicompartment modelling of drug binding to plasma proteins based on non‐linear saturation kinetics. Two‐ and three‐compartment solutions are described in more detail. The data concerning warfarin binding to rat plasma proteins fitted well to a three‐compartment model indicating two binding sites. The amount of free drug increased from 4 % at low concentration (less than 10 μg/ml) to 39 % at the highest concentration (500 μg/ml). The mean extravascular extracellular protein concentration and the size of extracellular space of the rat was calculated with constants obtained from the literature, and a curve was constructed describing the theoretical warfarin binding in extravascular extracellular space. The binding percentages of two binding systems for warfarin were calculated by means of graphic analysis for both plasma and interstitial fluid proteins. The percentage of the second binding system was greater than that of the first system at high total drug concentrations. The second binding system also had a more prominent role in the extravascular space than in plasma even at relatively low total warfarin concentrations. The present approach may provide a useful and practical way of calculating drug binding to extracellular proteins.
Influence of Age on Half‐life of Trimethoprim and Sulphadoxine in Goats
Authors: Nielsen Poul , Rasmussen Folke
Published: July 2010

Abstract The half‐life of trimethoprim is about 40 min. in adult goats and 4–5 times longer in newborn kids. During the neonatal period the half‐life decreases to the level found in adult goats when the body weight is about 10 kg corresponding to an age of 40–50 days. The half‐life of sulphadoxine is about 12 hours in adult goats and there is a tendency towards a longer half‐life in newborn and young kids, but the difference is not significant. The apparent volume of distribution for both trimethoprim and sulphadoxine is higher in newborn kids than in adult animals. The apparent volume of distribution for trimethoprim decreases during the neonatal period while that of sulphadoxine is nearly constant until an age of 16 weeks.
Effects of Hangover on Psychomotor Skills Related to Driving: Modification by Fructose and Glucose
Authors: Seppälä T. , Leino T. , Linnoila M. , Huttunen M. , YIikahri R.
Published: July 2010

AbstractThirty healthy male volunteers drank ethyl alcohol (1.75 g/kg) from 6 p. m. to 9 p. m., which resulted in hangover the next morning, and 10 subjects served as controls. The twenty subjects, who drank alcohol, received glucose or fructose during the same evening (1.0 g/kg) or on the following morning (0.5 g/kg). In the hangover phase psychomotor performance was recorded by a choice reaction test, two coordination tests and an attention test. The intensity of the hangover was graded subjectively and objectively. Blood ethanol, acetaldehyde and glucose concentrations were analysed. The testing procedure was repeated at 8, 10 and 12 a. m. Ethanol, administered alone, increased significantly the number of mistakes on the choice reaction test in hangover phase, but this effect was abolished by the simultaneous administration of sugar. On the other hand, after the combined administration of ethanol and sugars the number of mistakes and mistake percentage on one coordination test were increased. The etiology on the impaired psychomotor skill during the hangover period is probably not directly related to the pathophysiology of the hangover, as there was no correlation between the impairment of the psychomotor performance and the intensity of the hangover of the subjects.
Changes in the Hepatic Microsomal Enzyme Activity during Long‐term Ethanol Feeding in Rat
Authors: Luoma P. , Vorne M.
Published: July 2010

AbstractAddition of ethanol (15 % v/v) to drinking water caused significant changes in the hepatic microsomal metabolism of methylaniline and p‐nitrobenzoic acid, and in the microsomal protein and cytochrome P‐450 contents in the rat. The effect of ethanol on these parameters was time‐related, and maximal changes were measured after two weeks of drinking ethanol, after which the effect of ethanol diminished. Within this period the N‐demethylation of methyl‐aniline was increased by 63%, and nitroreduction of p‐nitrobenzoic acid was inhibited by 50%. The microsomal protein content was increased after two weeks of drinking ethanol by 30 %, and the cytochrome P‐450 content by 96 %. Glucose‐6‐phosphate dehydrogenase activity in the 105,000 ×g supernatant fraction was increased during the whole experiment and after drinking ethanol for ten weeks it was stimulated by 116%. The decreases in the effects caused by ethanol could be related to the development of liver damage during long‐term ethanol usage.
The Hepatic Glucuronate Pathway in the Rat after Treatment with 3,3′,5‐Triiodothyronine and Phenobarbital
Authors: Marselos Marios , Puhakainen Eino , Rantanen Tapio
Published: July 2010

AbstractThe hepatic D‐glucuronic acid pathway was studied in male rats after administration of 3, 3′, 5‐triidothyronine (20 μg intraperitoneally daily, for three weeks). Some of the key enzymes of the pathway showed decreased activities during hyperthyroidism. D‐glucuronolactone dehydrogenase, UDPglucuronosyltransferase and UDPglucuronic acid pyrophosphatase were not affected, whilst the activity of β‐glucuronidase was significantly increased. D‐Glucaric acid excretion in urine was enhanced and that of L‐ascorbic acid was decreased. Phenobarbital administered to hyperthyroid and euthyroid animals (80 mg/kg intraperitoneally, daily, for 3 days) did not markedly affect the differences in the enzyme activities between the two groups. UDP‐Glucuronosyltransferase and D‐glucuronolactone dehydrogenase activities were induced, and in the case of UDPglucuronosyltransferase the induction was more pronounced during hyperthyroidism. D‐Glucaric acid excretion in the urine was increased by phenobarbital treatment both in hyperthyroid and normal animals. L‐Ascorbic acid excretion was also increased, but the increase was greater in euthyroid than in hyperthyroid animals. The results suggest that hyperthyroidism favours the metabolism of free D‐glucuronic acid towards the formation of D‐glucaric acid. Treatment with phenobarbital, however, also enhances to some extent the biosynthesis of L‐ascorbic acid.
The Effect of Locally Applied Cholinesterase Inhibitors and Oximes on the Acetylcholinesterase Activity in Different Parts of the Guinea‐Pig Eye
Authors: Lund‐Karlsen R. , Fonnum F.
Published: July 2010

Abstract High activities of acetylcholinesterase and choline acetyltransferase were found in the guinea‐pig retina compared to the brain, and in the cornea, iris and the external eye muscles compared to striated muscles. Instillation of diisopropyl phosphorofluoridate (DFP), sarin and paraoxon into the conjunctival sack was followed by rapid inactivation of the acetylcholinesterase in the cornea and iris, whereas the enzyme activity in the retina and the external eye muscles were much less affected. The de novo synthesis of acetylcholinesterase in the iris and cornea was studied after irreversible inhibition of the enzyme by locally applied diisopropyl phosphorofluoridate following which 50 % of the enzyme activity returned to both regions after 7–10 days. Acetylcholinesterase inhibited by diisopropyl phosphorofluoridate, sarin or paraoxon could be reactivated by locally applied toxogonin or pyridine‐2‐aldoxime methyliodide. Benzalkonium in 0.03 % solution increased the degree of reactivation probably by increasing the permeability of the cornea.
Relative Bioavailability of Phenoxymethylpenicillin Preparations in a Cross‐Over Study
Authors: Bergan Tom , Berdal Bjørn Peter , Holm Vibeke
Published: July 2010

Abstract In a cross‐over study on 6 healthy volunteers, the serum concentrations and the bioavailability of 16 oral phenoxymethylpenicillin preparations have been compared. The dissolution rates of the tablets and capsules were studied. The preparations included 5 aquous solutions, 7 tablets or capsules, and 4 suspensions. The highest bioavailability was seen with the aquous solutions and the tablets or capsules containing the potassium salt of phenoxymethylpenicillin. Two calcium salt tablet brands showed lower serum mean concentrations and bioavailability than the other, potassium salt, tablets and capsules, but the differences were only statistically significant for one of the calcium salt tablets as compared to the tablet with the highest mean concentrations. The poorer bioavailability of the calcium salt tablets was reflected in longer dissolution times. The suspensions intended for paediatric use were significantly inferior to most of the other preparations. The lowest bioavailability was observed with a suspension containing the poorly soluble benzathine phenoxymethylpenicillin.
Concentration of Amphetamine Isomers in Brain and Heart of Adult and Developing Mice
Authors: Alhava Eeva
Published: July 2010

AbstractThe levels of d‐ and 1‐amphetamine in the brain and heart of adult and developing mice aged 3–6 days and 13–16 days were studied. More d‐ than 1‐isomer was found in the brain of developing mice, except after a dose of 100 mg/kg of the drug, i. e. a dose which produces a higher level of 1‐amphetamine in the brain of 13–16‐day‐old mice. Adult brain retained 1‐amphetamine in a higher concentration than d‐amphetamine. In the youngest mice 50 mg/kg of the isomers produced equal levels of the drug in the brain and heart, whereas 100 mg/kg of the d‐form was particularly concentrated in the infant heart. In the older age groups the brain level of either isomer was generally higher than the respective heart level. The age‐ and dose‐dependent differences in the distribution of amphetamine isomers emphasize the importance of peripheral component of amphetamine action in the youngest mice and reveal a low sensitivity of the central nervous system to 1‐amphetamine in 13–16‐day‐old as well as in adult mice.
Effect of Psychic Stress of Examination on Serum Growth Hormone, Serum Insulin, and Plasma Renin Activity
Authors: Syvälahti E. , Lammintausta R. , Pekkarinen A.
Published: July 2010

Abstract The levels of serum human growth hormone (HGH), immunoreactive insulin (IRI), blood glucose (BG), and plasma renin activity (PRA) in a total of 131 healthy voluntary medical students and in 83 control subjects were studied to find out whether the psychic stress of examination in pharmacology can affect the release of these hormones. The mean HGH level rose by 33 per cent after a written interim examination (P < 0.05) and by 49 per cent (P < 0.01) after a final oral examination. The mean IRI level rose by 45 per cent (P < 0.01) after a written examination and by 43 per cent (P < 0.01) after an oral examination. The mean BG level did not vary significantly. The rise in HGH and IRI was higher after short examination periods (< 60 minutes) than after longer examinations (< 90 minutes). The mean PRA rose by 44 per cent (P < 0.05) after a written and by 27 per cent (P < 0.05) after an oral examination, but the mean values of PRA after an examination were, however, within the normal range.
Studies on the Uptake of14C‐Neostigmine in the Isolated Rat Diaphragm
Authors: Helleberg Lars
Published: July 2010

AbstractThe uptake process of14C‐neostigmine in striated muscles was studied using the isolated rat diaphragm. Hemidiaphragms were incubated with 3 × 10‐7M14C‐neostigmine at 37° in Krebs‐Ringer solution containing 11 mM glucose and aerated with oxygenxarbon dioxide (95:5 v/v %). The uptake, which is expressed as the muscle‐to‐medium concentration ratio, was 1.41, after 3 hours, after which the rate of uptake diminished and became equal to that of inulin. The uptake which showed partial saturation, was decreased by some tertiary and quarternary amines, metabolic inhibitors, potassium and in an atmosphere of nitrogen. Neostigmine accumulated in all parts of the muscle without preference for the end plate zone. The half‐time for the efflux was about 30 min. The phrenic nerve‐diaphragm preparation became desensitized to the effect of 3 × 10‐7M neostigmine after 2–3 hours. It is suggested that the uptake of neostigmine is mediated via a specialized carrier transport system.
Cytochrome P‐450 and Drug‐induced Spectral Interactions in the Hepatic Microsomes of Trout, Salmo trutta lacustris*
Authors: Ahokas Jorma T. , Pelkonen Olavi , Kärki Niilo T.
Published: July 2010

Abstract The properties of various components of a drug‐oxidizing mono‐oxygenase system in the liver of trout (Salmo trutta lacustris) were studied. The concentration of the cytochrome P‐450 was about 7 nmol/g liver wet weight when measured in the 12,000 × g supernatant and 0.2 nmol/mg protein when measured in the “microsomal” fraction. The activity of NADPH‐cytochrome c reductase was about 2000 nmol cyt. c reduced/g liver/min. measured in the homogenate and 20 nmol/mg protein/min. when measured in the “microsomal” fraction. The distribution of the cytochrome P‐450 into different centrifugal fractions indicates that it is localized in the endoplasmic reticulum. The cytochrome P‐450 present in the fish liver microsomal fraction was capable of interacting with different substances resulting in type II (aniline, n‐octylamine, cyanide) and a reversed type I (n‐butanol) spectra. Substances producing type I spectra in the rat liver microsomes, did not give any spectra (hexobarbital, SKF 525A) or gave unclassified spectral changes with the fish liver cytochrome P‐450 (bromobenzene, DDT, piperonyl butoxide). Spectral dissociation constants were calculated for aniline and n‐octylamine. Further experiments indicated that the mono‐oxygenase system in the trout liver microsomes can metabolize aminopyrine, aldrin and 3,4‐benzpyrene.
Metabolism of Morphine in the Perfused Rat Liver
Authors: Dahlström B. E. , Jonsson J. , Paalzow L. K.
Published: July 2010

AbstractMorphine concentrations in the recirculating plasma of a perfused rat liver preparation declined in a monoexponential manner with a half–life of 5.3 ± 0.4 min. The mean hepatic clearance was calculated to 13.1 ± 1.0 ml–min.–1, and using an average blood flow of 17.3 ml min.–1this corresponds to an extraction ratio of 0.76 ± 0.02. In experiments with steady state concentration of morphine almost identical results were obtained. Measurements of different morphine concentrations in the in– and outflow of plasma of the liver yielded a mean clearance of 13.3 ± 0.7 ml–min.–1and a mean extraction ratio of 0.77 ± 0.03, indicating a constant clearance at different concentrations. The clearance of morphine in the perfused liver experiments was in close agreement with anin vivocalculated hepatic clearance of 75 % of the total body clearance. It is concluded that the blood flow to the liver can be an important factor in determining availability of orally administered morphine, and that the high hepatic extraction of this drug can explain the low effectiveness of this mode of administration.
Absorption, Distribution and Metabolism of Sulphafurazole and Chloramphenicol in Rats with Intestinal Occlusion
Authors: Venho V. M. K. , Mattila M. J.
Published: July 2010

AbstractThe rat small intestine was occluded at the ileocaecal junction, while control rats underwent sham–operation. 42–46 hours later sulphafurazole 50 mg/kg or chloramphenicol 250 mg/kg was given by gavage. The drug concentrations in the whole blood, small intestine, large intestine, liver, kidneys, lungs and heart at respectively 30 and 60 min. after sulphafurazole and at 60 min. after chloramphenicol administration were assayed chemically. Occlusion increased the absolute liver and small intestinal weights. The total sulphafurazole levels reached in blood and other tissues except the large intestine at 30 min. were about similar at 60 min. both in sham–operated and occlusion rats, but occlusion increased total sulphafurazole in the large intestine at 60 min. Occlusion increased acetyl sulphafurazole in the liver, kidneys and lungs at 60 min. and in the large intestine acetyl sulphafurazole was higher at 60 min. (about 60 %) than at 30 min. (about 30 %) in both sham–operated and occlusion rats. Occlusion did not significantly modify total chloramphenicol in any tissue or blood. Occlusion increased free and NO2–reduced chloramphenicol in the large intestine. It seems that occlusion does not alter the absorption or distribution of sulphafurazole and chloramphenicol, but modifies their inactivation by increasing metabolism and probably by altering their excretion through the large intestine.
The Effects of some Anticholinergic Compounds on the Infused Urinary Bladder of Anaesthetized Rabbits
Authors: Sjögren Christer
Published: July 2010

AbstractThe intravesical pressure and volume of the urinary bladder of anaesthetized rabbits were studied using a urinary bladder infusion technique. It was shown that the anticholinergic compounds used, atropine, emeprone, and PR 197, significantly increased the urinary bladder volume capacity, and that they decreased the micturition pressure. Atropine was the most potent compound in increasing the bladder volume capacity, followed by PR 197 and emeprone, mentioned in order of potency. Atropine and PR 197 increased the bladder volume capacity and the micturition threshold pressure significantly more than emeprone. There was no statistically significant difference between the effects of the different compounds on the residual volume or the micturition pressure. It is suggested that the effects of the compounds are confined mainly to the bladder and most probably to its cholinergic structures.
Response to Isoprenaline in the Human Pregnant and Non–pregnant Myometrium
Authors: Lossius K. , Nesheim B.–I.
Published: July 2010

AbstractStrips from human pregnant and non–pregnant uteri were examinedin vitro.The spontaneous contractions were more frequent in the strips from nonpregnant uteri. Isoprenaline inhibited the contractions of the strips from pregnant uteri, while the strips from non–pregnant uteri were much less sensitive to isoprenaline. Propranolol antagonised the effect of isoprenaline on strips from pregnant uteri, the dissociation constant for propranolol being of the magnitude 10–8. Carbacholine contracted the strips from non–pregnant uteri. The effects of isoprenaline on spontaneously contracting and carbacholine–contracted strips were compared quantitatively, and were found to be of the same order.
Action of Tsoprenaline, Isoxsuprine and Ritodrine in the Human Non–pregnant Myometrium
Authors: Berg–Johnsen P. , Nesheim B.–I.
Published: July 2010

AbstractThe effects of isoprenaline, isoxsuprine and ritodrine were tested on spontaneously contracting muscle strips from non–pregnant human uterusin vitro.The strips were rather insensitive to all three drugs, the maximal inhibitions obtained being: isoxsuprine (10–4M) 81 %, ritodrine (10–4M) 45 %, isoprenaline (10–5M) 19%. Propranolol 3.4 × 10–6M did not significantly block the effects of isoxsuprine and ritodrine. It is concluded that the non–pregnant human uterus is rather insentitive to β–adrenoceptor stimulation, and that isoxsuprine and ritodrine act mainly through unspecific mechanisms.
The Effect of N–acetyJated DL–penicillamine and DL–homocysteine Thiolactone on the Mercury Distribution in Adult Rats, Rat Foetuses and Macaca Monkeys after Exposure to Methyl Mercuric Chloride
Authors: Aaseth Jan , Wannag Axel , Norseth Tor
Published: July 2010

AbstractThe distribution and excretion of mercury was studied in pregnant rats, given a single intravenous dose of 2 μmol/kg of CH3203HgCl on the 13th day of pregnancy. Oral treatment for one week with N–acetyl–DL–penicillamine (4 mmol/kg per day) increased the mercury excretion in faeces (from 45 to 120 nmol) and urine (from 9 to 160 nmol). Such treatment mobilized mercury from all the organs tested, and the foetal and maternal brain levels of mercury were decreased to 1/5 and 1/3 of the controls, respectively. A four–day period of treatment with N–acetyl–DL–penicillamine started three days after the injection of methyl mercury reduced the foetal and maternal brain levels to 1/2 and 2/3 of the controls, respectively. The rapid removal of metal deposits following treatment with N–acetyl–DL–penicillamine is attributed to a free penetration of the complexing thiol into the tissue cells in question. No signs of toxicity were detected in monkeys given an effective daily dose of the agent (4 mmol/kg) for 6 days. In contrast N–acetyl–DL–homocysteine thiolactone was found to be toxic in the monkeys. In addition, the latter agent was ineffective in increasing the mercury elimination from the brains of monkeys, rats and rat foetuses.
Drug Absorption from the Small Intestine of the Triparanol–Treated Ratin Situ
Authors: Venho V. M. K.
Published: July 2010

AbstractThe effect of treatment with triparanol (25 mg/kg by gavage every 24 hours for three weeks) on the absorption of phenobarbitone, sulphafurazole, isoniazid, mecamylamine and quinidine from the rat small intestine was studiedin situby measuring their disappearance from the intestinal lumen. The appearance of sulphafurazole and mecamylamine in the intestinal lumen was also studied after their intravenous administration, and the partitioning of mecamylamine between the buffer solution and the intestinal tissue was measuredin vitro.Treatment with triparanol retarded the absorption of sulphafurazole, whereas the absorption of mecamylamine was accelerated. The amount of sulphafurazole and mecamylamine in the intestinal lumen after their intravenous administration was relatively slight. Thein vitropartitioning of mecamylamine into the intestinal tissue was higher in triparanol–treated than in control intestines. Triparanol did not change the absorption of phenobarbitone, isoniazid or quinidine. Phenobarbitone in the whole blood at the end of the experiment was increased after triparanol, but the levels of other drugs were unchanged. Triparanol did not modify drug concentrations in the intestinal wall at the end of the experiment. The relatively slight changes in drug absorption induced by triparanol are probably due to changes in the morphology and composition of the intestinal wall.
Inhibition of the Acetaldehyde Dehydrogenases in Rat Liver by a Cyanamide Derivative present in a Commercial Standard Diet for Small Animals
Authors: Marchner H. , Tottmar O.
Published: July 2010

AbstractThe inhibition of the acetaldehyde dehydrogenase activity in rat liver by an unknown dietary factor, present in a commercial standard diet for rats, was studied. The inhibitory factor was located in the calcinated bonemeal fraction of the diet and was identified by infrared spectrophotometry and thin–layer and paper chromatography as cyanamide or a cyanamide derivative. The occurrence and formation of cyanamide in calcinated bonemeal, its effects on the acetaldehyde dehydrogenases and the metabolism of acetaldehyde in rat liver, are discussed.
The Effect of some Sympathomimetic Amines and their Acetyl Derivatives on the Isolated Bull Retractor Penis Muscle
Authors: Marvola Martti , Friström Sinikka , Klinge Erik , Halmekoski Jaakko
Published: July 2010

AbstractThe bull retractor penis muscle was used to compare the α–adrenergic effect of adrenaline, noradrenaline, methoxamine, phenylephrine, metaraminol, tyramine, amphetamine, ephedrine and orciprenaline with that of some of their O– and N–acetyl derivatives. The effect of cocaine on the responses to the drugs was also examined. Methoxamine exhibited the strongest stimulant potency on this smooth muscle. The ED50of the other parent compounds decreased in the following order: adrenaline, noradrenaline, phenylephrine, ephedrine, metaraminol, amphetamine, tyramine. N–acetylation decreased very clearly or even abolished the effect of the drugs. O–acetylation also decreased the effect but not as much as N–acetylation. The effects of the O–acetyl derivatives were probably at least partly due to the corresponding parent compounds released after deacetylation. The very weak effects of the N–acetyl derivatives suggest that little if any N–deacetylation occurred during the experiments.
Antagonism of the Acute and Long–term Biochemical Effects of 4–Chloroamphetamine on the 5–HT Neurones in the Rat Brain by Inhibitors of the 5–Hydroxytryptamine Uptake
Authors: Ross Svante B.
Published: July 2010

AbstractThe effects of H 102/09 ((Z)–3–(4–bromophenyl)–N, N–dimethyl–3–(3–pyridyl)allylamine dihydrochloride) and chlorimipramine, two inhibitors of the membrane 5–hydroxytryptamine (5–HT) uptake, on the acute and long–term effects of 4–chloroamphetamine on the 5–HT neurones in rats were examined. The acute effect determined as the decrease in the brain level of 5–HT was antagonized by both compounds. The long–term effects determined as the decreases in 5–hydroxyindoles and the synaptosome accumulation of14–C–5–HT were antagonized by a single injection of H 102/09 (20 mg/kg intraperitoneally) immediately before or shortly after the 4–chloroamphetamine administration. Chlorimipramine, 40 mg/kg intraperitoneally, had no antagonizing effect but on repeated injections of 40 mg/kg intraperitoneally before and four times with 3 hours' intervals after 4–chloroamphetamine, a partial antagonism of the longterm decrease in 5–HT was obtained. Combined with proadifen (SK & F 525 A) chlorimipramine partially antagonized the long–term effect. Two monoamine oxidase inhibitors (pheniprazine and clorgyline), pretreatment of the rats with p–chlorophenylalanine (2 × 300 mg/kg intraperitoneally) or proadifen alone (40 mg/kg intraperitoneally injected before and four times with 3 hours' interval) had no antagonistic effect on the long–term decrease in 5–HT. The accumulation of3H–chloroamphetamine in synaptosomes of the hypothalamus midbrain region was slightly decreased by high concentrations of H 102/09 at 37° and 0°. H 102/09 decreased slightly but significantly the ratio between the3H–chloramphetamine in the synaptosomal fraction and the supernatant as obtained when the rats were killed 2 hours after the injection. The increased efflux of3H–5–HT from synaptosomesin vitroproduced by 4–chloroamphetamine, ouabain and low external Na+concentrations was in all cases inhibited by H 102/09 at 2.5 × 10–6M. Although the antagonism of the acute effect of 4–chloroamphetamine seems to be related to inhibition of the membrane 5–HT transport mechanism the antagonism of the long–term, irreversible effect produced by 4–chloroamphetamine may also involve an additional as yet unknown mechanism.
UDPGlucuronosyltransferase and Mixed Function Oxidase Activity in Microsomes Prepared by Differential Centrifugation and Calcium Aggregation
Authors: Aitio A. , Vainio H.
Published: July 2010

Abstract Microsomes were prepared from the liver, kidney and lung of phenobarbital or 20–methylcholanthrene treated and control rats with the conventional ultracentrifugation and calcium aggregation methods. The two methods were compared as to the yield of microsomal protein, amount of cytochrome P–450/448 and activity of UDPglucuronosyltransferase, benzopyrene hydroxylase and p–nitroanisole O–demethylase. The absolute amount of cytochrome P–450/448 (nmol/g wet weight), as well as the enzymatic activities dependent on it (nmol produced/g wet weight) did not differ significantly in any tissue of either treated or control animals nor did that of UDPglucuronosyltransferase. However, the ultracentrifugation method resulted in a slightly smaller yield of the hepatic microsomal protein and a correspondingly higher yield of cytochrome P–450/448 per mg protein as well as higher specific enzymatic activities of both the consecutive drug biotransformation reactions studied. The specific activity of UDPglucuronosyltransferase in digitonin treated microsomes was twice as high in the conventional microsomes as in the calcium aggregated microsomes; no differences was found in the trypsin treated microsomes. The specific activity of the hepatic benzpyrene hydroxylase of the benzpyrene treated animals in the calcium harvested microsomes was 55 per cent of that in the ultra–centrifugated microsomes.
Effect of Manganese on the Levels of DNA, RNA, DNase and RNase in Cerebrum, Cerebellum and Rest of Brain Regions of Rat
Authors: Shukla Girja S. , Chandra Satya V. , Seth Prahlad K.
Published: July 2010

Abstract Levels of DNA, RNA, DNase, RNase and manganese in different regions of rat brain were studied after daily administration of manganese chloride (8 mg MnCl2 4H2O/kg intraperitonealy) for a period of 120 days. DNA and RNA contents decreased significantly in cerebrum, cerebellum and rest of the brain regions after manganese treatment. A decrease in the DNase and an increase in the RNase activity was observed in the cerebellum and rest of brain region of the manganese treated animals. The manganese content increased significantly in all the regions of the brain, the maximum concentration being in the rest of brain portion. The presence of excess manganese in brain presumably leads to alterations in the functional activity of lysosomal enzymes. The decrease in the levels of nucleic acids is perhaps a consequence of the degenerating and dead neurones.
Influence of Various Anaesthetics on the Cardiovascular Responses to Noradrenaline in Rats before and after Guanethidine
Authors: Nielsen Gunnar Damgård
Published: July 2010

Abstract The influence of surgical anaesthesia induced by ketamine, pentobarbital, pentobarbital‐xylazine, or chloralose‐urethane on blood pressure and heart rate was studied, and the effects were compared with results in conscious and pithed rats. The blood pressure was significantly decreased by pentobarbital‐xylazine. The heart rate increased in all groups except in pentobarbital‐xylazine anaesthetized rats. Generally, a fall in heart rate and blood pressure was observed during a two hours lasting anaesthesia as compared to the initial values. The blood pressure response to noradrenaline was significantly lowered by ketamine, pentobarbital and chloralose‐urethane anaesthesia, and the response of the heart rate only by chloralose‐urethane. Guanethidine 5 mg/kg intravenously significantly lowered the blood pressure in the ketamine, pentobarbital and chloralose‐urethane anaesthetized groups. The guanethidine induced potentiation of the haemodynamic effects of noradrenaline was considerably influenced by the anaesthetic, the augmentation being greatest in pentobarbital and chloralose‐urethane anaesthetized rats. Chloralose‐urethane is considered a suitable anaesthetic in rats when studying the effects of noradrenaline and guanethidine. Following a single intraperitoneal injection a surgical anaesthesia of more than two hours' duration was obtained, and the variance of the parameters studied was less than that following administration of the other anaesthetics. It is emphasized that various effects of anaesthetics unrelated to their anaesthetic properties may obscure or even invalidate results obtained with drugs acting on the peripheral sympathetic nervous system.
Interaction of Perphenazine with the Kinetics of Nortriptyline
Authors: Overø K. Fredricson , Gram* L. F. , Hansen V.
Published: July 2010

AbstractThe kinetics of nortriptyline in four patients were investigated before and during treatment with perphenazine (24–36 mg/day) by administering 57 mg nortriptyline hydrochloride as an intravenous infusion and evaluating the resulting plasma concentration data according to a two compartment open model. In all patients an increased biological half‐life as well as a decreased systemic clearance and rate of metabolism were found in the perphenazine‐period, thus confirming the inhibitory effect of perphenazine on the metabolism of nortriptyline found in earlier studies. Some interaction with distribution parameters was also indicated, but on the whole the model parameters did not provide much further information about the interaction. Although the most pronounced changes were found with the patient getting the highest dose of perphenazine, the dose‐effect relationship remains obscure.
Potentiation by α‐Methyltyrosine of the Suppression of Food‐Reinforced Lever‐Pressing Behaviour Induced by Antipsychotic Drugs
Authors: Ahlenius Sven , Engel Jörgen
Published: July 2010

Abstract The mode of action whereby α‐methyltyrosine (α‐MT) potentiates the behavioural effects induced by catecholamine receptor blocking antipsychotic drugs was investigated in rats trained to lever‐press for food on a fixed‐ratio 40 schedule of reinforcement. It was found that α‐MT (20 mg/kg intraperitoneally ‐ 4 hrs potentiates the effects induced by pimozide (0.04 mg/kg intra‐peritoneally ‐ 6 hrs) which preferentially blocks central dopamine (DA) receptors, but not the effects induced by phenoxybenzamine (0.5 mg/kg intra‐peritoneally ‐ 30 min.) which blocks central noradrenaline (NA) receptors. Furthermore, the behavioural suppression induced by chlorpromazine (0.5 mg/kg intraperitoneally ‐ 15 min.), thioridazine (1.5 mg/kg intraperitoneally ‐ 15 min.), or haloperidol (0.02 mg/kg intraperitoneally ‐ 15 min.) were not potentiated by the administration of the inhibitor of DA‐β‐hydroxylase, bis‐(4‐methyl‐1‐homo‐piperazinylthiocarbonyl) disulfide (FLA‐63) (4 mg/kg subcutaneously ‐ 1 hr). The potentiation by α‐MT of the clinical effects of antipsychotic drugs and of their behavioural effects in animal experiments is in all probability due to a blockade by α‐MT of a feed‐back mediated compensatory increase in the catecholamine synthesis as a result of a blockade of central NA and/or DA receptors by the antipsychotic drugs. Since, in the present experiments, the behavioural effects induced by drugs which block central DA but not NA receptors were potentiated by the simultaneous administration of α‐MT, it seemed probable that the disruption of conditioned behaviours by antipsychotic drugs is due to a blockade of central DA receptors. In view of the fact that the ability to selectively disrupt conditioned behaviours is shared by a wide range of antipsychotic drugs differing in chemical structure and also in their mode of action, it is possible that a blockade of DA neurotransmission is also of primary importance for the clinical effects induced by antipsychotic drugs.
Methyldopa Binding to Cells in Culture
Authors: Dybing Erik
Published: July 2010

AbstractCells from a rat hepatoma grown in culture were found to activate methyldopa to intermediates which are bound irreversibly to cellular proteins. The binding reaction was not inhibited by superoxide dismutase or allopurinol, but was strongly inhibited by ascorbic acid and glutathione. Methyldopa, paracetamol and furosemide were not mutagenic in theSalmonella/mammalian‐ microsome mutagenicity test.
A Comparison of the Effects of Ouabain, Noradrenaline and Nifedipine on the Contractile Force of the Isolated Rat Atrium at Different Calcium Levels
Authors: Refsum Helge , Landmark Knud
Published: July 2010

AbstractThe effects of ouabain 5 × 10‐5M, noradrenaline 10‐7M and nifedipine 100 μg/1 on the contractile force of the isolated rat left atrium were tested and compared at varying concentrations of calcium in the Ringer solution. The effect of ouabain was small, developed slowly and almost independently of the calcium concentration. Noradrenaline, which increases Ca++influx during excitation, caused an increase in the contractile force which was complete within 2 min. The percentage as well as the absolute increase in contractile force was pronounced at lower, but small at higher calcium concentrations. Nifedipine, which reduces Ca++influx during excitation, caused a decrease in contractile force which was complete within 2–4 min. The nifedipine‐induced depression in contractile force decreased with a rise in the calcium concentration. It is assumed that the ouabain‐induced increase in contractile force in the rat, is not mediated by an increase in the magnitude of the inward calcium current, and other modes of action for the inotropic effect of glycosides are discussed.
Extraction and Metabolism of Lidocaine in Rat Liver
Authors: Nyberg Gunilla , Karlén Bo , Hedlund Inger , Grundin Robert , von Bahr Christer
Published: July 2010

AbstractThe use of lidocaine as an oral antiarrhythmic drug is limited by its rapid disposition in the liver. In accordance with this we found that the drug was completely extracted during one passage through the perfused rat liver. The drug binds to rat liver microsomes with a type I spectral change of unusually high affinity. It is rapidly de‐ethylated by the microsomes with an apparent Vmaxof about 15 nmol per mg protein × min. The apparent Kmfor this reaction is about 250 μM. The reaction occurres at about the same rate in isolated rat liver cells. We believe that the high affinity of lidocaine for the cytochrome P‐450 system, as indicated by its type I spectral change, as well as the rapid oxidation of the drug are the two main determinants for the marked liver extraction and first pass effect of the drug.
A Simple and Inexpensive Protein Binding Assay for Cyclic AMP in Biological Materials
Authors: Geisler A. , Klysner R. , Thams P. , Christensen S.
Published: July 2010

Abstract We have developed a simple and inexpensive method for largecapacity cAMP determination in biological materials. The assay is based on competitive binding of 3H‐cAMP to proteins isolated from rabbit skeletal muscle. Bovine serum albumin is added to the incubate to reduce non‐specific interference. Separation of free and bound radioactivity is performed by (NH4)2SO4 precipitation allowing determination of either free or bound fraction. In the latter case, all procedures are performed in the same tube, to which is finally added 1.2 ml of scintillation fluid for counting. By this one‐tube‐procedure a high precision is obtained and the expense per sample is reduced to approximately one fourth. The method has been applied to rat tissue extracts and urine with satisfactory sensitivity, precision and accuracy.
Effect of Propranolol and Related Drugs on Transmembraneous pH Differences in Liposomes
Authors: Åkerman Karl E. , Jårvisalo Jorma O.
Published: July 2010

AbstractPropranolol (1‐isopropylamino‐3‐(1‐naphtoloxy)‐propan‐2‐ol) a β‐adren‐ergic receptor blocking agent was found to cause changes of transmembraneous pH in liposomes prepared from Soy‐lecithin and cardiolipin. When the external pH was neutral and the internum of the liposomes acidic, the drug decreased the pH gradient. When the externum was acidic and the internum neutral, the gradient was increased by the drug. The effect of butacaine was similar to that of propranolol, while procaine, timolol and practolol were ineffective. It is suggested that the charged form of propranolol is bound to the membrane and dislocates protons from binding sites in the membrane and that the uncharged form of propranolol penetrates the membrane. After penetration it could associate with protons in the intraliposomal compartment and hence increase the pH of the interior. Depending on the direction of the pre‐existing proton gradient propranolol would thus be able to increase or decrease the pH difference across the liposomal membrane.
On the Aromatic Hydroxylation of Amphetamine in Rat Liver Microsomes and Perfused Liver Preparations: Effects of Long‐term Administration
Authors: Jonsson John
Published: July 2010

AbstractThe liver microsomal p‐hydroxylation of amphetamine to parahydr‐oxyamphetamine (pOHA) was dependent on NADP and inhibited by carbon monoxide indicating the involvement of cytochrome P‐450. SKF 525‐A, fenfluramine and desmethylimipramine were the most effective inhibitors of this pathway of amphetamine metabolism. Repeated administration of phenobarbital resulted in reduced p‐hydroxylation of amphetaminein vitro.Chronic administration of amphetamine reduced the microsomal p‐hydroxylation of amphetamine without apparent changes in the cytochrome P‐450 levels or in the activity of NADPH‐cytochrome c reductase. The aromatic hydroxylation of aniline and the demethylation of ethylmorphine was not affected by this treatment. However, the 455 nm complex formed during the microsomal metabolism of N‐hydroxy‐amphetamine was increased by the long‐term administration of amphetamine. These results indicate some pecularities of thein vitrohydroxylation of amphetamine by rat liver microsomes. Amphetamine disappeared from the perfusate of the perfused liver at the same rate in rats given a single dose of amphetamine and in rats given amphetamine orally for four weeks. The excretion of pOHA and its conjugate increased at 60 and 90 min. and 30, 60 and 90 min. respectively in the perfusate of the same experiment as compared to the controls. The total excretion of radioactive amphetamine metabolites at the end of the perfusion was increased in the perfusate and reduced in the bile compared to the control experiment.
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 MnCl2'4H20/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.
Chronic Administration of Cyanide: Urinary Excretion of Thiocyanate in Male and Female Rats
Authors: Mehta Chander S. , McGinity James W.
Published: July 2010

Abstract The urinary elimination of thiocyanate was investigated in male and female rats following the chronic administration of potassium cyanide. Female rats dosed at the level of 5 mg KCN/kg once a week and twice a week respectively, displayed no significant difference in the excretion of thiocyanate in urine after periods of up to eight weeks of study. Similarly, male rats that were administered 5 mg/KCN/kg twice weekly showed no significant difference in the amount of thiocyanate excreted. The elimination patterns of thiocyanate in male and female rats showed no significant differences. The results suggest that a substrate saturation phenomenon is not operative with cyanide metabolism at the dosage level of potassium cyanide employed in this study. This is contrary to a previously published study which reported that the urinary excretion of thiocyanate decreased after chronic potassium cyanide administration.