bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Cholinergic and Cholinergic Blocking Drugs on Decamethonium Uptake by Slices of Mouse Kidney
Authors: Holm Jan
Published: July 2010

The accumulation of decamethonium by mouse kidney slices was investigated with particular reference to the possibility that this agent uses a choline transport system. Slices of mice kidneys were incubated (1 hour) in Krebs‐Ringer bicarbonate medium (37°, pH 7.4) containing14C‐decamethonium (2 × 10‐6M) with or without the addition of other drugs. Choline and neostigmine stimulated decamethonium uptake at relatively low concentrations (10‐3M and 3 × 10‐3M choline, 5 × 10‐5M and 10‐4M neostigmine), whereas both agents at higher concentrations (3 × 10‐2M choline, 10‐3M and 10‐2M neostigmine) depressed the uptake. Hemicholinium‐3 (10‐3M), atropine (2 × 10‐5M) and physostigmine (2 × 10‐4M) inhibited decamethonium uptake, indicating that these agents in addition to choline and neostigmine share a common transport mechanism with decamethonium. The initial decamethonium influx (3 minutes incubation) could be stimulated by pre‐incubating the slices (1 hour) with 10‐3M choline or 3 × 10‐4M neostigmine (in the absence of decamethonium) before transfer to a final medium containing only decamethonium. Stimulation can thus be interpreted as an example of accelerative exchange diffusion, which should mean that efflux of choline or neostigmine accumulated by the slices accelerates decamethonium influx. It is concluded that decamethonium uses a specialized transport system, which seems to involve a choline carrier and to be in part at least identical with the system responsible for organic cation secretion by the intact kidney.
Studies on Riboflavin Metabolism in the Rat. V. Degradation of Riboflavin‐2‐14C
Authors: Christensen Sten
Published: July 2010

Riboflavin‐2‐14C was administered orally or intraperitoneally to female Wistar rats in order to study the metabolic fate of the vitamin. Almost all the radioactivity was found in the urine, faeces, carcass and expired CO2 within 24 hours. The chemical recovery of riboflavin was lower, indicating partial degradation. Approximately 1% of the radioactivity was recovered as 14CO2. Following oral administration more than half of the radioactivity excreted in the urine was in the form of metabolites. Paper chromatography of urine revealed three unidentified labelled metabolites. After intraperitoneal administration only negligible amounts of non‐riboflavin radioactivity were present in the urine. It is suggested from these data that the enzymes responsible for the degradation were saturated at the highest plasma concentrations reached. It is concluded that riboflavin, ingested orally within the dose range of 0.08 to 2.5 mg/rat, is eliminated to equal extents by degradation and by urinary excretion. This also seems to be the case at physiological conditions of vitamin intake.
Studies on Riboflavin Metabolism in the Rat. VI. Properties of Radioactive Metabolites Excreted after Administration of Riboflavin‐2‐14C
Authors: Christensen Sten
Published: July 2010

The radioactive metabolites excreted in the urine and faeces after administration of riboflavin‐214C to rats were investigated. Paper chromatography (n‐butanol:acetic acid:water 4:1:5) of urine indicated the presence of five radioactive metabolites. The average Rf‐values were 0.10, 0.20, 0.42, 0.53 and 0.63 respectively. Incubation of urine with urease indicated the presence of minute amounts of radioactive urea. The faeces contained two of the metabolites found in the urine. Metabolite Rf 0.63 was identified as lumichrome. The significance of its predominance in the faeces is discussed. Apart from the metabolite Rf 0.53, the excitation spectrum of which is presented, the metabolites did not fluoresce in an aqueous medium. They were more soluble in water than riboflavin. On a Sephadex G‐25 column they were eluted more rapidly than riboflavin. Hydrolysis experiments showed that none of the metabolites were conjugates of riboflavin.
Metabolism of 1,1,2‐Trichloroethane‐1,2‐14C in the Mouse
Authors: Yllner Sven
Published: July 2010

Labelled 1,1,2‐trichloroethane (0.38 μci/mg), prepared by chlorination of ethylene‐14C, was injected intraperitoneally (0.1–0.2 g/kg). The elimination of radioactivity was followed for 3 days. 73–87% of the dose was found in the urine, 0.1–2% in the faeces (contaminated by urine), and 16–22% in the expired air. About 3/5 of the expired activity was due to carbon dioxide and the remainder to unchanged trichloroethane. 1–3% of the dose remained in the animal. Examination of the urine by paper chromatography showed 3 major metabolites – chloroacetic acid, S‐carboxymethylcysteine and thiodiacetic acid – and small amounts of glycollic acid. The following amounts (per cent of the urinary activity) were estimated by isotope dilution analysis: chloroacetic acid 6–31, S‐carboxymethylcysteine 29–46 (free) and 3–10 (conjugated) and thiodiacetic acid 38–42. These results are in good agreement with those previously obtained by the administration of chloroacetic‐1‐14C acid. It may therefore be suggested that the metabolism of 1,1,2‐trichloroethane proceeds mainlyviachloroacetic acid. Isotope dilution analysis also revealed small amounts of 2,2‐dichloroethanol, 2,2,2‐trichloroethanol, oxalic acid and trichloroacetic acid in the urine.
On the Determination of Catechol‐O‐Methyltransferase Activity in Tissue Homogenates
Authors: Broch O. J. , Guldberg H. C.
Published: July 2010

A procedure for the spectrophotofluorimetric determination of catechol‐O‐methyltransferase (COMT) activity in crude tissue homogenates is described. The method is based on the known principle that the enzyme converts 3,4‐dihydroxyphenylacetic acid to homovanillic acid in the presence of S‐adenosyl methionine and magnesium ions. After incubation and simple organic solvent extractions, the end product is separated by paper chromatography before the development of the fluorophor. The characteristics of the enzyme kinetics using the present method were found to be in good agreement with those of previous studies using a purified COMT preparation. It was found that iodide could act as an inhibitor of COMT which has practical implications in that some commercial coenzyme preparations contain this ion. Some factors contributing to the discrepancies in the results obtained for COMT activity determinations by fluorimetric and radiochemical procedures were investigated and the sources of error discussed. The main advantage of the present fluorimetric method for COMT determinations is considered to be the applicability of the method to crude homogenates of tissues such as brain which have relatively low enzyme activity.
The Desorption of Medicinal Substances from Adsorbents in Oral Pharmaceutical Suspensions
Authors: Münzel Kurt
Published: July 2010

Abstract: In children the desorption of diazepam from an adsorbate in a suspension syrup and hence its biovailability is retarded as compared to that of a drop solution, although the anti‐pentetrazol‐test in mice could not reveal such a difference between these two dosage forms.
Interindividual Differences in the Protein Binding of Sulfonamides: The Effect of Disease and Drugs1,2
Authors: Anton Aron H. , Corey W. Theodore
Published: July 2010

Abstract:The variation in the plasma protein binding of sulfonamides in healthy adults was minimal. Additional evidence for consistency in binding came from a literature survey in which it was found that the plasma protein binding of several sulfonamides in man and laboratory animals was remarkably similar as reported by investigators from different countries. Some hospitalized patients, however, do show a binding deficiency which may be due to an interaction between drugs, disease and altered plasma proteins. Several drugs were found to compete with the sulfonamide for the same binding sites on the protein (albumin) molecule. The plasma protein binding of a sulfonamide in six anephric patients was studied before and after haemodialysis. As expected all showed a deficiency in binding. Unexpectedly, however, the binding was less in the post‐dialysis plasma sample in three patients. In some patients there appeared to be a qualitative and a quantitative change in the binding sites on the protein. More definitive studies are needed with plasma protein fractions from healthy and ill subjects in the presence and absence of drugs. This may lead to a better understanding of the side effects to some drugs and could result in the development of useful displacing agents.
Molecular Aspects of Drug Metabolism
Authors: Orrenius Sten
Published: July 2010

Abstract:Drug oxidation is linked to a liver‐microsomal electron transport system consisting of at least two components ‐ cytochrome P‐450 and the NADPH‐cytochrome P‐450 reductase. Cytochrome P‐450 is also involved in the hydroxylation of lipid‐soluble endogenous compounds, such as steroid hormones and fatty acids. Substrates capable of undergoing hydroxylation bind to cytochrome P‐450 and the reduction of the cytochrome P‐450‐substrate complex so formed may well be the rate‐limiting step in the over‐all hydroxylation process. It is suggested that the competitive inhibition that various substrates exert on each other's hydroxylation is due to a competition for binding to a common cytochrome P‐450 species in the liver microsomes.
Changes in the Effects of Hexobarbital in Male Rats Induced by Manipulations of Monoamines Through Reserpine or Pargyline Combined with DOPA or 5‐Hydroxytryptophane
Authors: Wahlström Göran
Published: July 2010

The sensitivity of rats to hexobarbital was measured in two ways: 1. By a threshold dose. Here the amount of hexobarbital needed to obtain a burst suppression of one second or more in the EEG was determined. 2. By ensuing anaesthesia times. The time at which the righting reflex was absent, after a threshold dose had been infused, was determined. Reserpine (2.5 mg/ kg subcutaneously) administered 0‐6 hours before the threshold determination, increased the threshold doses by approximately 20 per cent as compared to a pre‐experimental value. The ensuing periods of anaesthesia were then increased by 50 to 110 min. over the pre‐experimental values of around 20 min. The mono‐amine oxidase inhibitor pargyline (50 mg/kg subcutaneously) given alone one hour before the threshold determination had no effect on the threshold dose or on the ensuing periods of anaesthesia. If DOPA (6–12.5 mg/kg) was given 15 min. after pargyline the threshold doses were reduced by 50 per cent. A significant increase in the ensuing periods of anaesthesia of 40 min. was seen but only in the animals treated with 6 mg/kg DOPA, i.e. not if the higher dose had been used. 5‐hydroxytryptophane (5.0 mg/kg subcutaneously) was also given 15 min. after pargyline. This dose caused a decrease in the threshold by 20 %. The ensuing periods of anaesthesia was shortened by approximately 20 min. All animals died after 5‐hydroxytryptophane and pargyline. This mortality was not caused by the hexobarbital infusion. In normal individuals with widely varying threshold and even in barbiturate tolerant individuals, the ensuing periods of anaesthesia are very similar. This is in contrast to the results obtained in the present experiments.
Regional Disappearance of Catecholamines Formed from14C‐Tyrosine in Rat Brain: Effect of Synthesis Inhibitors and of Chlorpromazine
Authors: Nybäck Henrik
Published: July 2010

The disappearance of labelled catecholamines formedin vivofrom14C‐tyrosine in the whole rat brain and in different regions of the rat brain has been studied. The elimination of the labelled amines from the brain followed first order kinetics between one and ten hours after14C‐tyrosine administration. The half‐lives were 2.9 hours for14C‐dopamine and 5.3 hours for14C‐noradrenaline. The rate of disappearance of14C‐dopamine was highest in the cerebral cortex and striatum and lowest in the cerebellum. The rate of disappearance of14C‐noradrenaline was highest in the cerebellum and lowest in the diencephalon. The use of the disappearance of labelled catecholamines as a measure of turnover of endogenous amines is discussed on the basis of results obtained with the tyrosine hydroxylase inhibitor H 44/68 and the dopamine‐β‐hydroxylase inhibitor FLA 63. It is suggested that FLA 63 accelerates noradrenaline turnover and also affects dopamine neurons in the brain. In accordance with previous studies on the accumulation of labelled catecholamines formed from14C‐tyrosine in rat brain regions, chlorpromazine accelerated the disappearance of14C‐dopamine in the striatum but had no significant effect in the other regions. The disappearance of14C‐noradrenaline was not influenced by chlorpromazine in any of the regions studied. The results support the view that chlorpromazine accelerates dopamine turnover in the rat striatum.
Effect of Guanethidine on Nerve Cells and Small Intensely Fluorescent Cells in Sympathetic Ganglia of Newborn and Adult Rats
Authors: Eränkö Liisa , Eränkö Olavi
Published: July 2010

Newborn rats were given intraperitoneal injections of 20 mg/kg body weight of guanethidine daily for 8 days. About 3 weeks later, they were killed together with their untreated litter mate controls at the age of one month. Guanethidine caused destruction of the superior cervical and coeliac ganglia, the size of which was about 10% of that of the control ganglia. The number of nerve cells in the ganglion remnants was also reduced. The mean number of the small intensely fluorescent (SIF) cells of the superior cervical ganglion increased from 479 cells/ganglion to 1427, and those of the coeliac ganglion from 198 to 1071 cells/ganglion, after guanethidine administration. The number of SIF cells increased in normally existing clusters from which grew out finger‐like cell protrusions. Adult animals injected with 20 mg/kg body weight of guanethidine daily for 14 days and killed on the 15th day had superior cervical ganglia of slightly increased size. The space between the ganglion cell bodies was much increased and was infiltrated by numerous round‐nucleated cells, the cytoplasm of which was non‐fluorescent. The ganglion cells showed degenerative signs of varying degree, such as loss of basophilia and amine fluorescence. No increase in the number of SIF cells was observed. It is concluded that guanethidine causes a chemical sympathectomy accompanied by hyperplasia of the SIF cells in newborn rats, and severe degenerative changes with round cell infiltration in the sympathetic ganglia of adult rats.
Effect of Partial Liver Resection and Phenobarbital on the Restoration of Impaired Drug Metabolism in Carbon Tetrachloride Induced Liver Damage
Authors: Vorne Martti
Published: July 2010

The effect of partial liver resection and phenobarbital treatment on the restoration of hexobarbital,p‐nitrobenzoic acid andp‐nitrophenol metabolism and cytochrome P‐450 content in the rat liver was studied at different stages of liver damage after administration of carbon tetrachloride for 2, 4, 8, and 16 weeks. Restoration ofp‐nitrophenol conjugation was very rapid in the resected animals and 10 days after the liver resection there were no significant differences between the operated groups and unoperated saline controls. Phenobarbital increased the conjugative activity in the same way both in the controls and the carbon tetrachloride treated rats. The rate of metabolism ofp‐nitrobenzoic acid prior to and following liver resection was nearly the same as that of the unoperated controls up to 8 weeks. However, after 16 weeks of treatment the metabolism ofp‐nitrobenzoic acid was significantly lower than that in controls even 28 days after the liver resection. Phenobarbital treatment caused an increase in the reductase activity as early as after 8 weeks of treatment. Before resection the rate of hydroxylation of hexobarbital decreased progressively during carbon tetrachloride treatment. However, after resection the hydroxylation activity did not differ from that found in the resected controls up to 8 weeks, but 10 days after the resection the activity was only half or less as compared with the unoperated controls. Only after 16 weeks of treatment was the rate of metabolism of hexobarbital lower than that in the controls after partial hepatectomy. Phenobarbital treatment increased the rate of hydroxylation of hexobarbital. The change in cytochrome P‐450 content was nearly parallel to that of the rate of hexobarbital metabolism. Phenobarbital accelerated the restoration of cytochrome P‐450.
The Effect of Acetaldehyde on the Noradrenaline Content in the Isolated Heart from Normal and Disulfiram‐treated Guinea‐pigs
Authors: Møller Svend E.
Published: July 2010

Acetaldehyde causes an increase of noradrenaline (NA) content in the isolated heart, presumably due to an inhibition of monoamine oxidase. The isolated guinea‐pig heart does not accumulate normetanephrine; nor is this substance found in the perfusate. Acetaldehyde causes an increase of NA in the perfusate. In addition to increasing the NA content acetaldehyde acts by releasing NA from the heart.
The Effect of Oestrogenic Treatment on the Acid Mucopolysaccharide Pattern in Skin of Mice
Authors: Grosman Nina , Hvidberg Eigill , Schou Jens
Published: July 2010

Acid mucopolysaccharides obtained from the skin of the back of mice were determined after precipitation with cetylpyridinium chloride and cellulose‐column fractionation. The results are given as μmol uronic acid per gram dry fat free tissue. Following treatment with oestradiol monobenzoate the hyaluronic acid (HA) increased from 2.7 to 14.6, while the chondroitin sulphates were unaffected (3.7 to 4.2). The increase (from 1.3 to 10.8) of a fraction probably consisting of low molecular HA was considered as reflecting an intensified metabolic activity of HA in the connective tissue. A very close linear correlation (r = 0.924) was demonstrated between the increase in the high molecular HA and the increase in tissue water.
Chlorpromazine Inhibition ofp‐Aminophenol Glucuronidation by Rat Hepatoma Cells in Culture
Authors: Dybing Erik
Published: July 2010

Chlorpromazine (0.01 mM to 0.15 mM) inhibits the glucuronidation ofp‐aminophenol andp‐nitrophenol in a clonal strain of rat hepatoma cells, MH1C1, grown in culture, producing 50% inhibition ofp‐aminophenol glucuronidation in a serumfree incubation medium at 0.07 mM. Chlorpromazine, at concentrations of 0.05 mM to 1.0 mM, also inhibits the glucuronidation ofp‐aminophenol in a homogenate prepared from the rat hepatoma cells (50% inhibition at 0.25 mM); this inhibition was found to be non‐competitive. The effect of chlorpromazine is enhanced when serum is excluded from the incubations.
Effect of Intratesticular Injection of Lindane and Endrin on the Testes of Rats
Authors: Dikshith T. S. S. , Datta K. K.
Published: July 2010

Little is known about the action of different insecticides on the testicular tissue of animals. The administration of lindane and endrin into the rat testis produced hypertrophic and atrophic changes in the testis and induced total arrest of spermatogenesis. Unlike cytotoxic or alkylating agents, the action of these two insecticidal compounds was non‐specific to any group of spermatogenic cells. Intertubular and intratubular regions of the testis showed degenerative changes, necrosis and cellular proliferation. The seminiferous epithelium of the tubules was completely damaged. Formation of multinucleate giant cells of the foreign body type reaction was very common following lindane treatment. The number of spermatozoa and the percentage of deformed (abnormal) spermatozoa was very low after lindane administration as compared to that of endrin.
Thalidomide Teratology in Swine: A Preparatory Study
Authors: Jonsson B. Göran
Published: July 2010

Pregnant sows were given thalidomide, 1 or 100 mg/kg, from day 17 to day 57 of gestation. The substance was given orally (mixed in the food). During the test various haematological, enzymatic and clinical‐chemistry studies were made on the sows. The sows were left for normal farrow after which the piglets were autopsied and a skeletal examination was performed. Neither the clinical studies of the sows nor the subsequent examination of the piglets revealed any effects which could be attributed to the medication.
The Interaction between Theophylline and some Adrenergic α‐ and β‐Receptor Agonists Evaluated as Effect on the LD50 of Mice
Authors: Olsson O. A. Torsten
Published: July 2010

The toxic effects (LD50) of noradrenaline, adrenaline, isoprenaline and terbutaline have been evaluated in mice pretreated with theophylline (theophyllamine). Compared with saline pretreated animals, the sensitivity to noradrenaline and adrenaline is significantly lowered, but that to isoprenaline and terbutaline remains unchanged.
Reduction in42K‐Efflux from Rat Atria by Promazine and Thioridazine
Authors: Landmark Knud , Haffner Jon F. W. , Setekleiv Johannes
Published: July 2010

Rat left atria were suspended for one hour in Ringer solution containing approximately 6 μci/ml42K. They were then transferred to a constant flow apparatus and the42K‐efflux was determined by measuring the radioactivity in the effluent. The mechanical activity was recorded simultaneously. The atria were driven by electrical stimulation at 180 beats per min. In normal Ringer solution a constant decrease in potassium efflux, assumed to reflect the transfer of42K through the cell membranes, was obtained after about 15 min. The addition of promazine 5 × 10‐6M to 5 × 10‐5M and thioridazine 10‐5M to 5 × 10‐5M to the Ringer solution caused a dose dependent reduction in42K‐efflux and in the amplitude of the atrial contractions. A reduction in the extracellular potassium concentration decreased, while an increase of the extracellular potassium concentration increased the42K‐efflux. The per cent reduction in42K‐efflux caused by promazine 5 × 10‐5M was almost the same under these experimental conditions, whereas the depressant action of the drug on the atrial contractile force increased with increasing concentrations of potassium. No direct proportionality between the reduction in42K‐efflux and the reduction in contractile force caused by promazine was found. It is concluded that the decrease in42K‐efflux caused by the drug is due to a reduced membrane permeability for this ion, and that the decrease in contractile force can be dissociated from this effect.
The Action of Practolol on the Isolated Rat Atrium
Authors: Refsum Helge , Landmark Knud
Published: July 2010

The β‐receptor antagonism and the effects of practolol on the mechanical and electrical behaviour of isolated rat atria suspended in an organ bath have been investigated. Practolol produced a parallel shift to the right in the log. dose‐response curves of isoprenaline with no decrease in the maximal response, indicating that the antagonism is competitive. The drug was found to exert positive inotropic and chronotropic effects in doses between 10‐8M and 10‐5M. Practolol 10‐4M did not change the threshold for excitation and the threshold for experimentally induced atrial fibrillation to any extent, neither did it prolong the effective refractory period. The results show that practolol has β‐adrenergic receptor blocking properties as well as sympatomimetic properties. The results also indicate that practolol possesses no quinidine‐like or local anaesthetic activity.
Ultrastructure and Microsomal Protein Content of Mouse Liver Treated with Methyl Mercury *
Authors: Pekkanen Timo J. , Lindberg Lars‐Axel
Published: July 2010

Abstract:24 male NMRI mice weighing about 17 g each were divided into two equal groups. Group 1 was treated intraperitoneally with methyl mercury nitrate. The dose was 0.3 mg Hg/kg in 0.5 ml water. Group 2, which was kept as a control, was treated with 0.5 ml water intraperitoneally. After 7 days all the mice were sacrificed. As seen by electron microscopy, the smooth endoplasmic reticulum was proliferated and vesicular in all the mice treated with methyl mercury. The mean liver microsomal protein content was significantly increased in group 1 as compared to group 2 (the controls).
Age Dependent Changes in Nicotine Distribution in the Brain of the Mouse
Authors: Stålhandske Torbjörn , Slanina Premysl
Published: July 2010

Abstract:Mice of different ages, from newborn to 26‐day old, were injected intraperitoneally with 1 mg/kg of14C‐nicotine and the nicotine concentrations in the blood and brains were determined 10 minutes after the injection. In 3‐day old and 12‐day old mice the nicotine concentrations in the blood and brains were also determined 1, 2.5, 5, 20 and 60 minutes after the injection. In addition, the nicotine distribution in 3‐day old, 12‐day old and 26‐day old mice was studied by whole‐body autoradiography. The results showed that the ability of the brain to accumulate nicotine increases with age. In addition there were also changes in the distribution of nicotine within the brain.
Differences in Metabolic Behaviour and Liver Toxicity Between the Optical Isomers of Bufenadrine Hydrochloride, a Substituted Diphenhydramine, in the Rat
Authors: Hespe W. , Mulder D. , van Eeken C. J.
Published: July 2010

Abstract: Among the alkyl‐substituted amino ethers derived from diphenhydramine, bufenadrine, 2‐[(o‐tert‐butyl‐α‐phenylbenzyl)oxy]‐N,N‐dimethylethylamine, is a remarkable example of the role of structural factors in liver toxicity. Non‐published toxicological investigations with both optical isomers of this compound revealed that (–)bufenadrine is exclusively or mainly responsible for the toxic activities of the racemic compound. Metabolic studies in rats with both optical isomers labelled N‐14CH3 showed that after a single dose profound differences already occur with regard to their metabolic fate. Over the period studied the elimination of radioactivity after a dose of both 2 mg/kg, intravenously, and of 10 mg/kg, orally, of the (–)isomer was lower in the urine, faeces and bile and higher in the respiratory air than with the (+)isomer. When an oral dose of 50 mg/kg was given, the elimination in the respiratory air, too, was lowest in the case of the (–)isomer. Since no significant difference in binding to serum constituents or to homogenated liver tissue was observed, it seems likely that the metabolic differences originate in the liver. The data obtained suggest the inability of the liver to metabolize (–)bufen‐adrine at a rate sufficient to prevent the accumulation of the substance which triggers off the toxic mechanism.
Amphetamine Toxicity in Adult and Developing Mice
Authors: Alhava Eeva
Published: July 2010

Abstract:The dose‐mortality curves for dl‐amphetamine after intraperitoneal administration of 10–180 mg/kg of it to adult and developing mice in 7 age groups from 3 to 30 days were determined. The dose‐mortality curve of adult mice was polyphasic. A 100 % mortality was obtained with 100 mg/kg of amphetamine. In developing mice the curves, polyphasic as well, were shifted to the right. At the age of 3 days the mortality caused by 180 mg/kg was only 68 %. With increasing age the animals became more sensitive to the drug, responding partially like the adults from the age of 18 days. The toxicity calculated in relation to the surface area remained unchanged, although the differences between the age groups of developing mice became smaller. In adult mice, pretreatment with 5 mg/kg of amphetamine protected against subsequent toxic doses of the drug, especially in the lower dosage range. Pretreatment given 4 hours before the toxic doses afforded the best protection. It is assumed that the immature CNS of developing mice is partially responsible for the increased tolerance to the drug. The polyphasic shape of the graphs and the protection afforded by the pretreatment reflect the complex lethal actions of amphetamine.
Age and Brain Catecholamine Content as Factors Influencing Amphetamine Toxicity in Mice
Authors: Alhava Eeva , Klinge Erik
Published: July 2010

Abstract:The brain noradrenaline (NA) and dopamine (DA) content of adult and developing mice of 3 age groups (3–5, 13–15 and 32–35 days) was assayed and found to increase with age. In adult mice 4 hrs after the administration of 50 mg/kg of amphetamine the brain NA content was decreased by 65 %. After 100 mg/kg of amphetamine the mice died in 25 min., but the NA and DA levels were only slightly decreased. In all age groups of developing mice, the doses of amphetamine sufficient to be lethal in 30 min. (100–160 mg/kg) caused only a slight decrease or even an increase in brain NA and DA levels. In developing mice surviving 60 min. after amphetamine, the brain amines were massively depleted. In adult mice the brain NA content in 1 hr and 4 hrs after the pretreatment dose of 5 mg/kg of amphetamine decreased by 20 %. The dose of 60 mg/kg 4 hrs after the pretreatment caused a massive depletion in brain NA and DA content 1 hr after the latter injection. Even though the mice survived. The lack of correlation between brain catecholamine depletion and amphetamine toxicity reflects the complex lethal mechanisms induced by the drug.
4‐Methylpyrazole as an Inhibitor of Ethanol Metabolism: Differential Metabolic and Central Nervous Effects
Authors: Rydberg Ulf , Neri Aldo
Published: July 2010

Abstract:The properties of 4‐methylpyrazole (4‐MP) as an inhibitor of ethanol metabolism were investigated in rats. No effect was seen on enzymatic determination of ethanol. 4‐MP in doses of 0.0053–3.0 mmol/kg brought about a competitive inhibition of the metabolism of 32.6 mmol ethanol per kg body weight ranging from 20.8 to 80.5 %. A dose of 0.017 mmol 4‐MP per kg gave an inhibition of 50 %. By varying the interval between the administration of 4‐MP and ethanol from 15 min. to 48 hrs, it was found that the inhibitory effect disappeared after 12 hrs. The influence of 4‐MP on ethanol‐induced incoordination was measured by a modified tilting‐plane technique. The mean maximal impairment was significant in all conditions, when compared to the controls. For ethanol alone the mean maximal impairment was 11.9 %, for 4‐MP alone 7.2 % and for ethanol + 4‐MP 14.9 %, the effect lasting for 8 hrs. Thus, 4‐MP exerts significant central depressant effectsper se, and produces an enhancement and a prolongation of ethanol‐induced effects on coordination in the rat.
Increased Specificity of the3H‐Acetic Anhydride Coupling Method for Plasma Analysis of Drugs Containing Secondary Amino Groups
Authors: Overø K. Fredricson
Published: July 2010

Abstract:For the plasma analysis of drugs containing primary or secondary amino groups the method of HAMMER & BRODIE (1967) has been widely used. By this technique amines are isolated by extraction and coupled with3H‐acetic anhydride. After removal of excess labelling agent, the amount of labelled coupling product is assayed by liquid scintillation counting. The possibility of masking primary amines by adding salicylic aldehyde to the hexane phase in the first extraction step of this method has been investigated. The presence of 0.1 M salicylic aldehyde was found to reduce considerably the amount of primary amine measured as3H‐amide, while secondary amines were only slightly influenced. Thus increased specifity for secondary amines was achieved. The practical importance of the modified method was illustrated by experiments on plasma from rats given nortriptyline and human subjects given Lu 5‐003, a bicyclic thymoleptic. In the former case the modified method is of less importance, since no primary amine metabolite is present ‐ in the latter case, however, it would be advantageous, because the corresponding primary amine is present as a metabolite in plasma.
Hexoestrol Analogues as Probes of Oestrogen Receptors I. Importance of Hydrogen‐Bonding Groups for Receptor Binding
Authors: Terenius Lars
Published: July 2010

Abstract:Analogues of the synthetic oestrogenmeso‐hexoestrol with systematically varied p,p'‐substituents were prepared. The competitive affinity of these analogues for the soluble oestrogen “receptor” molecules from mouse uterus were then measured. The results showed that thep,p'‐hydroxyls ofmeso‐hexoe strol are very important for affiinty. Substitution of one of the hydroxyls as in the OH,NH2; OH,CH2OH; OH,OCH3; OH,F or OH,H analogues lessened the binding affinities 15 to 90% while the OH,COOH analogue had < 99 % the binding affinity ofmeso‐hexoestrol. Replacement of both hydroxyls of hexoestrol as in the H,H; OCH3,OCH3; CH2OH,CH2OH; NH2,NH2; SH,SH or NHSO2CH3, NHSO‐2CH3analogues led to very marked reduction in affinity (> 99.9 %). Hydrogen‐bonding interchange at two spatially well‐defined sites seems to attach the oestrogen to the receptor. One of these bonds evidently has a higher energy of formation than the other.
Metabolism of Xenobiotics by Strains of Intestinal Bacteria
Authors: Soleim Harald A. , Scheline Ronald R.
Published: July 2010

Abstract:The metabolism of some xenobiotic compounds when incubated with strains of intestinal bacteria has been studied. The reactions included: 1) glucuronide hydrolysis, 2) glucoside hydrolysis, 3) sulphate ester hydrolysis, 4) glycine conjugate hydrolysis, 5) N‐acetyl derivative hydrolysis, 6) amide hydrolysis, 7) ester hydrolysis, 8) dehydroxylation, 9) decarboxylation, 10) double bond reduction, 11) nitro reduction, 12) azo reduction and 13) heterocyclic ring scission. The results showed that strains of the following test microorganisms were able to carry out the indicated reactions to varying degrees:Str. faecalis(4, 11, 12),E. coli(1, 11, 12),Lactobacillus(2, 10, 11, 12),Bacillus(9, 11, 12),Ps. aeruginosa(12),Pr. vulgaris(2, 10, 11, 12), A. aerogenes (2, 3, 4, 5, 9, 11, 12, 13), Clostridium (10, 11, 12)and Bacteroides(1, 11, 12). These results are discussed in relation to earlier findings on the metabolism of xenobiotics by members of the intestinal microflora.
Antagonism of Methylphenidate‐Induced Stereotyped Gnawing in Mice
Authors: Pedersen V. , Christensen A. V.
Published: July 2010

Abstract:It was observed by chance that methylphenidate induces an intense stereotyped gnawing in mice. Amphetamine too, induces stereotyped behaviour in mice, but this behaviour is mainly characterized by licking and rapid movements of the head and forelegs. Thus, the behavioural effects of amphetamine and methylphenidate in mice seem to be different under certain experimental conditions. The effect of methylphenidate was not blocked by pretreatment with dopamine‐β‐hydroxylase inhibitors and phenoxybenzamine, while the dopamine receptor blocking neuroleptics caused a complete inhibition. These findings support the view that brain dopamine is associated with production of stereotyped behaviour. Pretreatment with the tyrosine hydroxylase inhibitor d,1‐α‐methyltyrosine methylester (H 44/68) 1, 2 or 3 hours before methylphenidate caused no or only partial inhibition of the stimulant effect. Pretreatment with H 44/68 5 hours before methylphenidate completely inhibited the development of compulsive gnawing, indicating that the antagonistic effect of H 44/68 seems to be correlated with gross depletion of catecholamines from the brain. Reserpine too, was found to inhibit the effect of methylphenidate. A series of centrally acting drugs were tested for antagonistic effect of methylphenidate and only the neuroleptics proved to be active. A classification of 20 neuroleptics with respect to their methylphenidate antagonistic effect is presented. The clinically potent neuroleptics were active in very low doses, but the weaker “basal” neuroleptics like chlorpromazine and thioridazine also showed a clearcut effect.
Inhibition of Histamine Release and Formation of Slow Reacting Substance by Polyphloretin Phosphate
Authors: Strandberg Kjell
Published: July 2010

Abstract:Polyphloretin phosphate (PPP), a compound with prostaglandin and enzyme inhibitory activities, inhibited the release of histamine from rat mast cells induced by compound 48/80 or bee venom but had no effect on the release of histamine produced by chlorpromazine or n‐decylamine. In perfused cat paws (compound 48/80) and in guinea pig lung tissue (antigen) the histamine release and the formation of slow reacting substance were both inhibited by PPP. The blood pressure lowering effect of compound 48/80 in the cat was antagonized by the intravenous administration of PPP. Experiments with fractionated (dialysed) PPP showed that the high molecular weight fractions of PPP were more potent that the low molecular weight fractions in inhibiting histamine release from rat mast cells. Polyphloroglucinol phosphate, a polymer of the same type as PPP but devoid of any prostaglandin inhibitory (IPG) activity, inhibited the release processes in a manner similar to PPP, indicating that the IPG‐activity of PPP is not associated with its capacity to inhibit release. It is suggested that the inhibition by PPP of the release processes studied may be due, at least partly, to a chemical interaction between inhibitor and releasing agent.
The Fate of Atropine in the Puppy
Authors: Winbladh B.
Published: July 2010

Abstract:The fate of atropine in newborn, 3 and 6 weeks‐old, 3 months‐old and adult dogs has been investigated with the tritium‐labelled drug. After subcutaneous injection (0.5 mg/kg) maximal plasma concentrations of radioactivity were obtained after 0.5 hr in the two oldest groups and after 1‐1.5 hrs in the three youngest groups. The plasma half‐life of radioactivity was considerably longer in the newborn animals than in the other groups (11.5 hrs as against 3.5‐5.5 hrs). In the three youngest age groups, the urinary excretion of radioactivity was about half that in the adult animals, who excreted about 40 per cent of the injected radioactivity in 4 hrs. Between 50‐90 per cent of the radioactivity in the urine was recovered as the unchanged drug in all age groups in the 2 to 4 hrs interval. There were no consistent differences in the pattern of metabolites in the urine between the different age groups. The concentration of radioactivity in the liver, kidney, submandibular gland, heart, skeletal muscle and brain was investigated at 0.5, 1, 2, 4 and 8 hrs after injection (0.5, 2 and 8 hrs for adult animals). In general, there were no significant differences in organ distribution between the age groups. The radioactivity in the brain consisted exclusively of the unchanged drug. The rate of penetration into the brain and the maximal brain concentrations of the drug showed no significant changes with age. Within the hemispheres, a fall in the concentration of atropine from the cerebral cortex to the lateral ventricles was found in all age groups. The binding of atropine to plasma proteins was about 18 per cent over a wide range of concentrations. No difference in plasma bindingin vivowas found between the different age groups.
The Enzymatic Hydrolysis of a Series of Aminoacylanilides in Relation to their Nerve Blocking Effect and Toxicity
Authors: Åkerman S. B. A. , Ross S. B. , Telč A.
Published: July 2010

Abstract:Evidence has been adduced that in a series of aminoacylanilides the extent to which enzymatic hydrolysis is effected by liver amidases is dependent on the steric positions of substituents. The significance of hydrolysis for the detoxification of aminoacylanilides was examined by repeated administration of the compounds at a slow rate to rabbits. Compounds that were rapidly broken down by amidases displayed a lower cumulative toxicity than those resistent to the enzymes. On the other hand, there was no evident correlation between the enzymatic activity and the acute intravenous or subcutaneous toxicity (LD50 values) following rapid injection of large doses. The toxic potency in this case was directly releated to the blocking action on the isolated nerve. In the case ofo‐toluidine derivatives, there was a close correlation between the rate of hydrolysisin vitroand the formation of methaemoglobin. With 2,6‐xylidine derivatives, no significant formation of methaemoglobin was observed in spite of rapid hydrolysis.
Inhibition of Carrageenin‐Induced Rat Paw Oedema by Catecholamines and Amine‐Depleting Drugs
Authors: Arntzen Finn Cato , Briseid Kjell
Published: July 2010

Abstract:The anti‐inflammatory effects of adrenaline, isoprenaline, noradrenaline, tyramine, reserpine, guanethidine and fibrinolysin®were tested against carrageenin‐induced rat paw oedema. All the substances significantly inhibited the oedema. The inhibition by tyramine enhanced the effect of reserpine. The MAO‐inhibitor iproniazid potentiated the effect of noradrenaline and reduced the effect of reserpine. Thein vivoeffects of adrenaline, noradrenaline, reserpine and fibrinolysin on parameters of the plasma kinin system were investigated. Neither kininogen nor prekallikrein was influenced by any of the substances tested. The effect of noradrenaline, reserpine and guanethidine on the blood serotonin level was also investigated. Noradrenaline and guanethidine did not influence the serotonin level under experimental conditions which cause a significant reduction in the carrageenin‐induced rat paw oedema. The depletion by reserpine of the serotonin stores did not correlate with the rat paw oedema inhibition values. Nevertheless, a slight reduction in the blood concentration of serotonin after pedal injection of carrageenin might indicate a local release of the amine. Finally, plasminogen was estimated by a caseinolytic procedure in the plasma of rats injected with noradrenaline. Noradrenaline inhibited the rat paw oedema, but no reduction of the plasminogen level was observed. It was concluded that normal catecholamine stores rather than normal serotonin stores, and the application to the blood platelet serotonin, seemed essential for the development of carrageenin‐induced rat paw oedema. The fact that pretreatment with catecholamines inhibited the development of oedema might suggest that the same pathway of biochemical events is involved in the inflammatory process and in the preventive mechanism, the inhibition then reflecting an acute activation and depletion of a factor later in the sequence.
Uptake and Retention of the Enantiomers of a Local Anaesthetic in Isolated Nerve in Relation to Different Degrees of Blocking of Nervous Conduction
Authors: Åkerman B.
Published: July 2010

Abstract:Sciatic nerves of the frog were soaked with equimolar solutions of the3H‐enantiomers of compound RAC 109, a spirosuccinimide with local anaesthetic action. The enantiomers were taken up equally by. (1) sheathed nerves during 2 hrs soaking with 2.5 mM solutions, (2) sheathed nerves and 10 min. soaking with 1.25‐40.0 mM solutions and (3) desheathed nerves during 1 hr soaking with 0.25 mM solutions. The washout curves for the two forms after application (2.5 mM) to sheathed nerves for 1 hr were identical. Recording of the block of the action potential with simultaneous determination of the concentration of the compound in sheathed nerve revealed a difference in the rate of block (5.0 mM) and the depth of block at equilibrium (2.5 mM) between the enantiomers, but the same uptake and retention in nerve. The epineural sheath was not a stereo‐selective barrier to penetration. Series of equilibrium blocks with 0.01‐0.4 mM3H‐enantiomers showed an approximately four‐fold difference in concentration in de‐sheathed nerve with a 50 per cent block of nervous conduction. The enantiomer RAC 109 I was consistently more potent than RAC 109 II. The findings suggest that the difference in the nerve blocking potency of the enantiomers can hardly be ascribed to a difference in the uptake of the compounds by nerve.
Anti‐Nociceptive Activity of Some Thiophthalanes with Morphine‐like Properties
Authors: Fjalland B. , Pedersen V. , Lassen N. , Petersen P. V. , Nielsen I. Møller
Published: July 2010

Abstract:The anti‐nociceptive activity of a series of thiophthalanes and some related compounds has been compared to that of five known anti‐nociceptive drugs. Among the series several compounds were found to possess typical morphine‐like properties. They were as active as morphine in various anti‐nociceptive tests in mice, produced a Straub‐Herrmann tail reaction and their anti‐nociceptive activity was antagonized by nalorphine. The most potent compound of this series was 3,3‐dimethyl‐1‐dimethylaminoethyl‐1‐phenylthiophthalane (Lu 6‐062). The corresponding sulphoxide and the sulphone were slightly less active, but showed a faster onset of effect. Thus, it is suggested that the effect of Lu 6‐062 may be mediated through the sulphoxide metabolite.
Drug Infusion into the Spinal Subarachnoid Space of Unanaesthetized Rats during Early Postnatal Life: A Technique for the Study of Brain Development
Authors: Bass Norman H. , Lundborg Per
Published: July 2010

Abstract:A convenient and rapid method for percutaneous catheterization of the spinal subarachnoid space of rats is described. The technique is particularly suited for the study of brain development and enables the investigator to infuse drugs intrathecally into unanesthetized animals during early postnatal life. At the termination of a five minute infusion of 40 and 90 microliters of Evans blue dye to five and thirty day old rats, respectively, complete penetration of the subarachnoid space and ventricular system is found. A similar infusion of carboxyl‐14C inulin to thirty day old animals results in an immediate and equal distribution of radioactivity to both sides of the brain. In five day old rats, a similar symmetrical distribution occurs within 30 minutes. In both groups of animals, a three‐fold elevation of spinal fluid pressure is found immediately after infusion, which rapidly decreases to normal resting levels within 10 minutes. In contrast to earlier cerebroventricular injection techniques, the present method avoids the problem of unequal distribution gradients created when drugs are infused near the periventricular region.
Biological and Pharmacokinetic Evidence for Generic Equivalence of Three Imipramine Preparations: Comparison with a New Imipramine Analogue
Authors: Tuck J. Richard , Kahan Elisabeth , Siwers Bo
Published: July 2010

Abstract:The biological availability of three imipramine preparations and an imipramine analogue, Leo 640, has been studied using a recently developed biological procedure. The isolated rat iris, was used to elucidate the inhibitory power of these drugs on noradrenaline uptake into adrenergic nerve terminals. Irides incubated in patients’ plasma before and during drug treatment were compared in two series of cross‐over studies on hospitalized patients. It was found that the drugs compared seemed to be identical with regard to their effect on noradrenaline neurons. It has been hypothesized that the antidepressive effect of this type of tricyclic drugs is brought about by their inhibition of reuptake of monoamines released into central synapses. This method provides a new way for comparing these drugs and their active metabolites at the presumed site of action.