bluuebunny/crossref_metadata_2025 huggingface dataset:
Adrenergic Receptors in the Guinea Pig Trachea and Lung
Authors: Persson Henry , Johnson Birgitta
Published: July 2010

The effect of adrenaline, noradrenaline, and isoprenaline was studiedin vitroon the spirally‐cut trachea and in anaesthetized animalsin vivo. In thein vitrostudies, all agents caused a relaxation of the tracheal muscles, and the relative potencies were in descending order, isoprenaline (142.2), adrenaline (21.9), and noradrenaline (1.0). After pretreatment for 20 minutes with propranolol (> 0.5 μg/ml) or INPEA (> 3 μg/ml) adrenaline and noradrenaline caused a contraction of the tracheal muscles. The effect of noradrenaline was 0.44 times that of adrenaline. The constrictor effect of adrenaline and noradrenaline was antagonized or completely inhibited by the α‐receptor blocking agents phenoxy‐benzamine and dibenamine in a concentration of 1–5 μg/ml. Isoprenaline did not produce any contraction of the tracheal muscles after pretreatment with propranolol or INPEA. In thein vivostudies, the animals were anaesthetized with pentobarbital sodium (50 mg/kg intraperitoneally). Intravenous injections were made into the right jugular vein. Changes in tidal volume were recorded according to the method of KONZETT & RÖSSLER. Adrenaline, in the doses 2–4 μg/kg, produced a weak bronchoconstriction that was enhanced after pretreatment of the animals with propranolol (2 mg/kg). The bronchoconstrictor effect of adrenaline and noradrenaline was not affected by atropine but was inhibited by phenoxybenzamine or dibenamine (1–2 mg/kg). Isoprenaline in doses up to 0.1 mg/kg did not produce any bronchoconstriction after pretreatment with propranolol. The results obtained suggest that the smooth muscles in the guinea‐pig trachea and lung contain both α‐ and β‐receptors, the β‐receptor being dominant.
Comparison between the Absorption of Nicotinic Acid and Pentaerythritol Tetranicotinate (Perycit®) from Ordinary and Enterocoated Tablets
Authors: Svedmyr Nils , Harthon Lennart
Published: July 2010

Nicotinic acid was shown to be rapidly absorbed from the gastrointestinal tract but also rapidly eliminated from the blood stream. Administration of nicotinic acid was therefore associated with large fluctuations of nicotinic acid concentration in the plasma. Two alternative ways of maintaining a moderate but more constant increase of the nicotinic acid concentration in the blood were studied. One way was to give nicotinic acid as a “sustained release” preparation. Nicotinic acid in enterocoated tablets with dissolution times of 2 hrs (in simulated intestinal juice), induced only an irregular and transitory increase of the plasma nicotinic acid concentration after 5 hrs and in some subjects only a reduction in plasma FFA. Enterocoated tablets with a dissolution time of 4 hrs were ineffective. Nicotinic acid is a weak acid and as such is poorly absorbed from the more distal parts of the digestive tract. Therefore the biological prerequisites for this alternative method were not so good. The second alternative method studied was to give a nicotinic acid ester which would continuously release nicotinic acid in the body. The nicotinic acid ester used (pentaerythritol tetranicotinate, perycit®, Bofors) given in an oral dose of 1 g, was found to give a moderate but consistent and prolonged increase in the free nicotinic acid concentration and a consistent decrease in the FFA‐level of plasma with a moderate flush. Nicotinic acid in ordinary tablets and in an equivalent dose induced a considerably more pronounced flush and a somewhat larger reduction in plasma FFA which however was of shorter duration. The decrease was accompanied by a secondary and prolonged elevation of the plasma FFA concentration. This secondary increase was not observed in the experiments with pentaerythritol tetranicotinate. The possible importance of these differences from a pharmacotherapeutical point of view is discussed.
Metabolism, Distribution and Excretion of the Thiophthalane Lu 5‐003, a Bicyclic Thymoleptic
Authors: Overø K. Fredricson , Jørgensen A. , Hansen V.
Published: July 2010

The metabolism of orally administered Lu 5‐003 has been studied in the rat, dog and man. Urine and faeces were studied by thin layer chromatography of basic and acidic extracts. The metabolic degradation was shown to proceed partly by sulphoxidation and partly by demethylation followed by deamination of the side chain. Seven metabolites were found. The pattern was the same in the three species investigated. A semiquantitative determination showed Lu 5‐003 and the demethylated metabolite to be the main excretion products in the faeces, while the more water soluble sulphoxides of these compounds and propionic acid derivatives were dominant in the urine.14C‐labelled Lu 5‐003, given intravenously to rats, was used for distribution and excretion studies. Groups of three rats were killed at different times after administration and the amount of radioactivity was determined in the blood and tissues. The distribution was shown to follow the well known pattern of psychotropic drugs i. e. high concentrations in the lungs, liver, kidneys and heart, while the brain concentration was considerably lower. Lu 5‐003 and its demethyl derivative constituted the main part of radioactivity in the organs as shown by thin layer chromatography of basic extracts. Up to 1 hour after administration Lu 5‐003 was the main compound in the brain, but this was exceeded later by the demethylated metabolite. The half‐life of radioactivity in the blood and brain was calculated to be about 2 hours. After a single dose 60 % and 23 % of the radioactivity was excreted in the faeces and urine respectively in 7 days, while 1 % remained in the body. During the first 24 hours 72.6 % was excreted. There was evidence of an enterohepatic circulation. Expired CO2showed minute amounts of radioactivity shortly after administration, probably originating from impurities.
Maximal Tolerated Daily Doses of Dicophane
Authors: Boyd E. M. , Lin F. M.
Published: July 2010

Dicophane was given by intragastric cannula to young male albino rats in daily doses of from 43 to 250 mg/kg for 100 days or until 90 % of the animals had died. The LDO (100 days) or maximal dose which killed no animals when given daily for 100 days was 42.8 ± 1.6 mg/kg/day, the LD50 (100 days) was 64.8 ± 1.4 mg/kg/day and the minimal LD100 (100 days) was 97.1 ± 2.8 mg/kg/day. The 100‐day LD50 index, or the LD50 (100 days) expressed as a percentage of the acute, oral LD50 (1 dose) was 17.6 ± 0.4. During the first 21 days of administration, the clinical signs of intoxication were similar to those recorded in studies on acute toxicity with single lethal doses. Clinical signs in 21 day‐survivors were limited to polydipsia, diuresis, aciduria, and some loss of body weight. Autopsy at 100 days revealed degenerative changes in the kidneys, liver and testes, a stress reaction, hypertrophy of the liver and gastrointestinal organs, and capillary congestion and loss of weight (with variable changes in water content) of many body organs. The 100‐day multiposal (subacute, chronic) toxicity of dicophane was similar to that of non‐narcotic analgesics such as aspirin, phenacetin and paracetamol.
The Blood Pressure Response Following Angiotensin in Nephrectomized, Urethanized Rats
Authors: Skinhøj Annette
Published: July 2010

The increase in blood pressure is short lasting in normal rats after supramaximal repeated doses of angiotensin and long lasting in nephrectomized rats anaesthetized with urethane. Twenty minutes after the administration of 2.5–7.5 μg per kg hypertensin® intravenously during 7.3 min. the increase in blood pressure in 4 animals nephrectomized 4–7 hours previously was 7 ± 1 mmHg and in 6 animals nephrectomized 18–24 hours previously was 13 ± 2 mmHg. No prolonged effect on the blood pressure was seen in animals nephrectomized 30–45 min. previously or in nephrectomized animals anaesthetized with amobarbital. Epinephrectomy or 1 mg per kg phenoxybenzamine prevented the long lasting effect of angiotensin. No correlation was found between the initial blood pressure and the production of a prolonged rise in blood pressure.
The Uptake of Decamethonium and Hexamethonium by Slices of Mouse Kidney
Authors: Holm Jan
Published: July 2010

The renal uptake of decamethonium was studied and compared to that of hexamethonium. Incubations were carried out at 37° in a medium with pH 7.4 containing 14C‐decamethonium (1.8 μM) and the uptake expressed as the slice‐to‐medium concentration ratio (S/M ratio) was measured. In an atmosphere of oxygen the S/M ratio which was 9 after 1 hour of incubation continued to increase during a 3 hour period, whereas in an atmosphere of nitrogen the S/M ratio reached a constant value of about 1 within 1/2 hour. The S/M ratio of 14C‐hexamethonium (2.0 μM), was 0.7–0.8 after 1 hour and approximated to one after 2 hours. The anaerobic uptake of decamethonium is directly proportional to the decamethonium concentration of the medium, whereas this is not the case with the aerobic uptake. The decamethonium uptake, which was markedly inhibited at 24° and in the presence of metabolic inhibitors, was depressed by hexamethonium and tetraethylammonium. The radioactivity extracted corresponded chromatographically to authentic decamethonium. It is concluded that decamethonium is taken up against a concentration gradient by a partly energy dependent process, which follows saturation kinetics and is inhibited by various mono‐ and bisquaternary compounds.
The Protective Action of Different Barbituric Acid Derivatives against Anoxia in Mice
Authors: Wilhjelm Bendt J. , Jacobsen E.
Published: July 2010

The protective action of eight different barbituric acid derivatives against anoxia was investigated in mice. The increase in survival time ranged between 0 % and 180 %. Three drugs was given in both equimolar‐ and equipotent doses; for these drugs the increase in survival time ranged between 50 % and 180 %, indicating that the difference in protective action depends on differences between the miscellaneous barbituric acid derivatives.
The Plasma Protein Binding of Amphetamine, Catecholamines and Related Compounds
Authors: Franksson Gunhild , Änggård Erik
Published: July 2010

The plasma protein binding of amphetamine, phenmetrazine, adrenaline, noradrenaline, dopamine, normetanephrine and metanephrine was studied using equilibrium dialysis with human plasma. The binding of amphetamine and phenmetrazine at 5 × 10‐7M to 5 × 10‐5M was about 20 %. No difference in the binding of amphetamine was found between drug non dependent and tolerant dependent subjects. At physiological concentrations (< 10‐6M) adrenaline was bound to about 20 %, noradrenaline and dopamine to about 13 %. The binding of metanephrine and normetanephrine was of a lower order, i. e. about 5 %. The results are of value for the understanding of the overall pharmacodynamic situation in amphetamine dependence.
In Vitro Studies on the Uptake of14C‐Labelled Decamethonium and Hexamethonium in Mouse Liver
Authors: Christensen C. Broen
Published: July 2010

The uptake process of14C‐decamethonium in liver was studied by measuring its uptake in slices incubated in Krebs‐Ringer bicarbonate medium (37°, pH 7.4) and for comparison the14C‐hexamethonium uptake was measured. At 2 μM the slice‐to‐medium (S/M) ratio for decamethonium was about 3 after 1 hour and continued to increase. The hexamethonium uptake after 1 hour was only 1/3 of the decamethonium uptake. Slices from female and immature male mice accumulated decamethonium to the same extent as slices from male mice, whereas rat liver slices were unable to concentrate decamethonium. In an atmosphere of nitrogen and in the presence of 1 μM 2,4‐dinitrophenol, iodoacetic acid or cyanide the decamethonium uptake was significantly reduced. With increasing concentration of decamethonium the 1‐hour S/M ratio decreased towards a constant value (1.5). Thus the uptake could be divided into a passive and a saturable process. The latter had a maximum capacity of 81 μM kg‐1, h‐1and a half saturation concentration of 54 μM. With 2 μM the decamethonium S/M ratio was reduced to about 50 % in the presence of 50 μM d‐tubocurarine. The inhibitory effect of 22 μM d‐tubocurarine decreased with increasing decamethonium concentration in accordance with competitive antagonism.
Further Pharmacological Studies of Bicyclic Thymoleptics
Authors: Petersen P. V. , Lassen N. , Ammitzbøll T. , Nielsen I. Møller , Nymark M. , Pedersen V. , Franck K. F.
Published: July 2010

The reserpine antagonistic and noradrenaline (NA) potentiating activities of 19 phthalane and 18 thiophthalane derivatives have been compared with those of 7 known tricyclic thymoleptics. Thirty minutes after an intraperitoneal injection of the test compound to mice, reserpine (2 mg/kg intraperitoneally) was given and one hour later the degree of ptosis was scored. The activity of each compound was expressed as the dose (mg/kg intraperitoneally) that reduced the ptotic score to half that of control mice (ED50). The NA potentiating effect was estimated in the pithed rat preparation. A small submaximally active dose (0.05 μg/kg intravenously) of NA was given as standard. After the intravenous injection of the test drug, the augmentation of the NA pressor response was calculated as a percentage of the initial value. The ED50 was read from a dose‐effect curve. It was found that 3,3‐dimethyl‐1‐(3‐aminopropyl) substituted phthalanes and thiophthalanes with a phenyl group or certain other electro‐negative, non‐cyclic groups in position 1, were the most potent reserpine antagonists and NA potentiators. The most interesting compounds were Lu 3–010 (3,3‐dimethyl‐1‐(3‐methylaminopropyl)‐1‐phenyl‐phthalane), Lu 4–012 (3,3‐dimethyl‐1‐(3‐methylaminopropyl)‐1‐cyano‐phthalane) and Lu 5‐003 (3,3‐dimethyl‐1‐(3‐methylaminopropyl)‐1‐phenyl‐thiophthalane), which showed marked reserpine antagonism and NA potentiation, but which were without any neuroleptic properties and had very weak anticholinergic effects.
Paraquat Poisoning
Authors: Tompsett S. L.
Published: July 2010

This paper deals with the development of methods for the detection and determination of the weed‐killer, paraquat, in body fluids (urine, blood, gastric aspirate, dialysates) and tissues. These have been obtained from 6 cases of paraquat poisoning (2 of which were fatal) admitted to hospital and from several other negative cases. A specific colour reaction is described for the detection and determination of paraquat. Thus when sodium hydrogen carbonate followed by sodium dithionite is added to the test solution, a blue colour is produced. The detection limit is about 1 microgram/ml. Following admission to hospital shortly after the ingestion of paraquat, the reaction can be applied directly to diluted urine and diluted (filtered) gastric aspirate. Paraquat can be detected in small quantities in urine for quite a long period after ingestion. It is necessary, however, to use a column of a cation exchange resin to achieve concentration and also to remove any interfering substances. Under these conditions, it is preferable to assess the absorbance of the blue colour on a recording spectrophotometer. The concentration of paraquat in the blood serum is extremely low and only detectable shortly after ingestion. It has been extremely difficult to detect any traces of paraquat in dialysates (haemo‐ and peritoneal). Depending on the interval of time between ingestion and death, paraquat may be detected in some tissues e. g. liver and kidney. Using the cation exchange resin technique, paraquat in quantities of 50 to 100 micrograms added to 100 ml of urine can be recovered with an accuracy of 86 to 91 %.
Drug Induced Changes in3H‐Catecholamine Accumulation after3H‐Tyrosine
Authors: Persson Torgny
Published: July 2010

The accumulation of3H‐DA and3H‐NA in the caudate nucleus, remainder of the brain, spinal cord and heart was measured 15 minutes after3H‐tyrosine administered intravenously into rats pretreated with drugs. Apomor‐phine as well as stimulating DA receptors reduced3H‐DA when given shortly before3H‐tyrosine, probably due to a negative feed‐back. When given 30 minutes or 3 hours previously,3H‐NA was increased, probably indicating the importance of DA neurone activity for NA activity. Clonidine which stimulates NA receptors, did not significantly reduce3H‐NA as expected by feed‐back. Pimozide, which blocks DA but apparently not NA receptors, not only increased3H‐DA but also3H‐NA. Haloperidol and chlorpromazine which block DA and NA receptors, only increased3H‐DA. Thioridazine, however, also increased3H‐NA. The complicated balance between the tendency for an increase of NA turnover by the direct feed‐back mechanism, and the counteracting inhibition from a reduced stimulation from the DA neurones, seems to be a contributary factor. LSD which stimulates the 5‐HT receptors increased the3H‐catecholamines both centrally and peripherally. The effect of d‐amphetamine was studied in some experiments, the most striking effect being an increase in3H‐DA after an intravenous injection of the drug. Lithium carbonate increased3H‐NA and probably also3H‐DA. Phenoxybenzamine, which blocks NA receptors, increased3H‐NA via feed‐back regulation.
Toxicity Studies with Fluindarol, 2‐[p‐(trifluoromethyl)phenyl]1, 3‐indandione, an Agent with Anticoagulant Properties (BS 7616 D)
Authors: van Eeken C. J. , Birtwhistle R. D. R. , Mulder D.
Published: July 2010

The phenylindandione derivative fluindarol was subjected to a toxicological investigation in view of its possible use as an anticoagulant in man. The acute oral LD50 in rats and rabbits was 198 and 123 mg/kg, respectively. The acute intraperitoneal LD50 in the rat was 125 mg/kg. Dogs survived single oral doses of up to 2810 mg/kg; if the drug was given for four consecutive days, an oral LD50 of 118 mg/kg was obtained. In a four‐week experiment in the rat, doses ranging from 108 to 7 mg/kg caused mortality which occurred sooner and more frequently in the females than the males; the organs showed haemorrhages and at the higher dose levels the liver showed parenchymal necrosis. Similar results were obtained with chlorindione, which tended to be somewhat less toxic. It was confirmed that a distinction should be made between the “toxicity” of an anticoagulant which is due to its pharmacological properties and true organ toxicity. Fluindarol was considered too toxic for clinical use.
Effects of Tetraethylthiuram Disulphide (Disulfiram), Diethyldithiocarbamate and Ethanol on Factors of the Kinin System in Human Blood
Authors: Venneröd Anne Marie
Published: July 2010

Tetraethylthiuram disulphide (disulfiram) and diethyldithiocarbamate were tested for kininase‐inhibiting effect (in vitro experiments). Disulfiram was found to be a potent inhibitor of human erythrocyte kininase (inhibition obtained at 25 μg/ml incubation mixture), but it did not inhibit human plasma kininase (in concentrations up to 200 μg/ml). Diethyldithiocarbamate was a potent inhibitor of plasma kininase (inhibition obtained at 25–50 μg/ml), but had a weaker effect on erythrocyte kininase (100–200 μg/ml being required for inhibition). Ethanol in the concentration range 5–10 % (w/v) was found to release kinin in human citrated plasma stabilized with EDTA‐2Na, 4 mg per ml. In minor concentrations (0.5–4% (w/v) were tested) ethanol potentiated the kinin‐releasing effect of ellagic acid. Comparative determinations were made of kininase, prekallikrein, total kininogen, kininogen fractions, and the rate of release of kinin in the plasma from 3 males on disulfiram‐treatment (daily dose 0.2 g) and also from untreated males. The results did not show any differences between the two groups.
A Source of Error in Catecholamine Turnover Studies with Labelled DOPA: Slow Disappearance of the Precursor
Authors: Persson Torgny , Waldeck Bertil
Published: July 2010

Rats were injected with 5 μg/kg L‐DOPA, ring‐2, 5, 6‐3H. At various time intervals the animals were killed and the levels of3H‐DOPA,3H‐3‐methoxytyrosine (MTyr),3H‐noradrenaline (NA) and3H‐dopamine (DA) in different tissues were determined after separation on alumina and DOWEX 50 × 4 columns. The specificity of the radioactivity in the DOPA and MTyr fractions was checked by radiopaper chromatography.3H‐DOPA appeared to decrease almost uniformly in the different tissues examined. The concentration of3H‐DOPA in the brain was low relative to the plasma and other tissues. The levels of3H‐DOPA and3H‐NA in the brain were of the same order of magnitude and the compounds disappeared at about the same rate from the tissue. In the heart3H‐DA disappeared more slowly than3H‐DOPA. The femoral muscle showed the largest accumulation of3H‐DOPA. There was no correlation between the extent of3H‐DOPA accumulation and the density of the adrenergic innervation. The data show that after injection of3H‐DOPA, this compound and the intermediate product3H‐DA are present for several hours in amounts sufficient to invalidate estimations of the true turnover of NA.3H‐MTyr was eliminated very slowly from the organism.
Time Course of the Demethylation of Trimethadione
Authors: Frey H.‐H. , Schulz R.
Published: July 2010

A gas chromatographic method for the determination of trimethadione in the serum is described. By this method, the time course of the demethylation of trimethadione to dimethadione, the latter being determined by UV‐spectrophotometry, was followed in mice and dogs. For the demethylation of trimethadione, a half‐life of 45 min. in mice and of 8 hours in dogs was found. The dimethadione formed is excreted extremely slowly: half‐lives were about 30 hours in mice and 50–80 hours in dogs. During chronic treatment dimethadione accumulates: with daily doses of 22–23 mg/kg trimethadione dimethadione concentrations of 175 to 225 μg/ml, while with doses of 64 mg/kg concentrations of about 400 μg/ml were reached in dogs. Under these conditions, unmetabolized trimethadione does not contribute more than 15 per cent maximally to the total anticonvulsant effect of treatment, and the determination of the serum concentrations of dimethadione is therefore considered sufficient for control of therapy.
Displacement of Brain and Heart Noradrenaline byp‐Hydroxynorephedrine after Administration ofp‐Hydroxyamphetamine
Authors: Lewander Tommy
Published: July 2010

After the administration ofp‐hydroxyamphetamine 20 mg/kg intraperitoneally, there was a 50 per cent decrease in the brain noradrenaline (NA) level and a 70 per cent decrease in the heart NA level at 4–8 hours after the injection. Control levels of brain and heart NA were reached at 96–144 hours after a single dose of the drug. Repeated injections ofp‐hydroxyamphetamine, 20 mg/kg twice daily for 3 days, caused a depletion of brain and heart NA to about 20 per cent of the control levels. The brain dopamine (DA) level was reduced to 85 per cent of the control level at 1 hour after 20 mg/kg of the drug and to 76 per cent after 40 mg/kg. After the repeated injections ofp‐OH‐A, the brain DA was reduced to 70 per cent of the control level. Radioactively labelledp‐hydroxynorephedrine was isolated from both brain and heart tissue extracts after the administration ofp‐hydroxyamphetamine‐3H. Parahydroxynorephedrine‐3H remained in the brain and the heart as long as the NA levels were decreased. The NA deficit in the brain and heart corresponded approximately to the amounts ofp‐hydroxynorephedrine‐3H present in the tissues. In reserpine pretreated rats the amounts ofp‐hydroxynorephedrine‐3H formed in the brain and heart tissues were reduced, indicating thatp‐hydroxynorephedrine is bound by a reserpine sensitive storage mechanism. Administration ofp‐hydroxyamphetamine or amphetamine accelerated the disappearance of labelledp‐hydroxynorephedrine from the brain and the heart.
The Effect of Thioridazine and Promazine in Reducing the Potassium Loss from Isolated Perfused Rat Hearts
Authors: Landmark Knud
Published: July 2010

Electrically stimulated isolated rat hearts were perfused with a Ringer solution containing a low concentration of K+. At the end of a control period of 20 min. the cumulative K+loss from the hearts was approximately 30 meq./kg dry weight. This value was used in each experiment as reference (100 per cent) for the total loss found after a subsequent additional test period of 30 min. The addition of promazine and thioridazine to the perfusate at the end of the control period reduced the further K+loss. The values found in the different groups at the end of the test period were: Control group (10 hearts): 154 ± 11.6 per cent; with promazine 10‐5M added (8 hearts): 103 ± 5.6 per cent; with promazine 2.5 × 10‐5M added (10 hearts): 74 ± 10.5 per cent and with thioridazine 10‐5M added (8 hearts): 110 ± 5.8 per cent. In another type of experiments, ouabain 1.5 × 10‐6M was added at the end of the control period. This drug caused an increased K+loss (181 ± 14.2 per cent) and ventricular fibrillation in 6 out of 8 hearts. Promazine 2.5 × 10‐5M added before ouabain, prevented the development of fibrillation in another group of 7 hearts, and also markedly reduced the K+loss. It is concluded that phenothiazines reduce the K+permeability of the heart muscle membranes.
The Hyperglycaemic Activity of Some Catecholamines and the Effect of α‐ and β‐Adrenergic Blocking Compounds in the Mouse
Authors: Hermansen Keld , Hyttel Inge
Published: July 2010

In order to classify the receptors involved in the hyperglycaemic response to catecholamines in the mouse, the relative potency of noradrenaline, adrenaline and isoprenaline in the induction of hyperglycaemia has been tested by giving increasing doses from 10 μg/kg to 1 mg/kg of one of the amines intraperitoneally. Following catecholamine administration the maximal concentration of glucose in the blood occurred between 10 and 30 min. and amounted to about 300 mg%. The relative potency was: adrenaline > noradrenaline while isoprenaline was inactive. The antagonistic effect on adrenaline induced hyperglycaemia of the α‐adrenergic blocking compounds: phenoxybenzamine HCl (dibenzyline®) and phentolamine (regitin®) and the β‐adrenergic blocking compounds: 1‐(isopropylamino)‐3‐(o‐phenoxyphenoxy)‐2‐propanol (Ph QA 33) and propranolol were tested by giving 1 and 10 mg/kg intraperitoneally 30 min. before the administration of adrenaline. Only phentolamine at the highest dose level was capable of preventing the hyperglycaemic response to adrenaline. Phenoxybenzamine, Ph QA 33 and propranolol proved to be inactive. It is concluded that the mechanism of adrenaline induced hyperglycaemia in mice cannot be explained simply by an α‐ and/or β‐receptor activation.
Determination of Thioxanthenes in Plasma at Therapeutic Concentrations
Authors: Mjöorndal T. , Oreland L.
Published: July 2010

A method for measuring thioxanthenes at therapeutic levels in plasma, based on the measurement of the fluorescence of the oxidized drugs, has been developed. The method permits estimation of about 3 ng of the drug. The disappearance of the drug from the plasma was followed after intravenous administration to rabbits and oral administration of a therapeutic dose to human volunteers. N‐demethylthiothixene is identified as a metabolite of thiothixene in man.
Metabolism, Distribution and Excretion of Flupenthixol Decanoate in Dogs and Rats
Authors: Jøorgensen A. , Overøo K. Fredricson , Hansen V.
Published: July 2010

The metabolism of flupenthixol decanoate administered in viscoleo® by intramuscular or subcutaneous injection has been studied by thin‐layer chromatographic techniques after extraction of urine, faeces and organs from dogs and rats. Since only minute amounts of the compound itself were detected in the organs and a high hydrolytic activity of blood and organs was demonstrated byin vitroexperiments, it was concluded that the compound is hydrolyzed in the organism. The flupenthixol thus formed was found to be metabolized by sulphoxidation and by dealkylation in the side chain following the same pattern as that previously shown for flupenthixol. The neuroleptic effect seen in the pharmacological studies is presumably due to flupenthixol, since this is quantitatively by far the most important substance found in brain extracts. In order to study the depot effect of the preparation, blood levels and excretion were followed after administration of the3H‐labelled compound. These studies indicated, that a sustained release of drug from a depot was obtained. The presence of a relatively limited depot was demonstrated.
Biotransformation of Methyl Mercuric Salts in the Mouse Studied by Specific Determination of Inorganic Mercury
Authors: Norseth Tor
Published: July 2010

Biotransformation of methyl mercuric chloride in the mouse was followed by the specific determination of inorganic mercury after a single injection of the organomercurial. Inorganic mercury was detected in the blood, brain, liver, kidney, spleen and in the intestinal cells. Inorganic mercury was also found in the bile and faeces. The results indicate a role of biotransformation in the excretion of mercury after the injection of methyl mercuric salts. Inorganic mercury was preferentially excreted in the faeces. Differences in pharmacokinetics of methyl mercuric salts between rats and mice have been discussed with regard to differences in biliary excretion and enterohepatic circulation. The importance of taking into account species differences in the evaluation of toxic hazards of methyl mercuric salts has thus been demonstrated.
Acute in Vitro Effect of Progesterone Dissolved in Dimethyl Sulphoxide on Isotonic Contractions and Electrical Potentials of Isolated Uteri from Early Pregnant or Hormone Pre‐Treated Rats
Authors: Einer‐Jensen N.
Published: July 2010

Spontaneous isotonic contractions and electrical activity were obtained from 3 cm sections of rat uteri placed in a 6 ml organ bath. The electrical activity was recorded by means of 2 pairs of platinum wire electrodes, each pair measuring the activity over a 2 to 4 mm uterus section. Uteri were used from 21 pregnant rats (length of pregnancy was 1 to 8 days) and from 4 non‐pregnant rats pre‐treated for 6 or 8 days with 10 mg/kg progesterone subcutaneously. When 0.17 vol % dimethyl sulphoxide (DMSO) was added to the organ bath no or only small changes in the electrical activity and the spontaneous contractions of the myometrium were observed. Administration of progesterone (83 μg per ml organ bath) dissolved in DMSO (50 mg/ml) inhibited the contractions after 10 to 60 seconds, but no or only minor changes were registered in the electrical activity. After DMSO‐progesterone solution had been washed out, the contractions reappeared after 7 to 20 minutes.
The 100‐Day LD50 Index of Captan
Authors: Boyd Eldon M. , Carsky Eva
Published: July 2010

Captan was given by gavage in a range of doses once daily for 100 days to young male albino rats. The oral LD50 (100 days) ± S. E. M. or daily dose which killed 50 % of rats over this period was found to be 0.92 ± 0.23 g/kg/day. The oral 100‐day LD50 index, or oral LD50 (100 days) expressed as a percentage of the acute oral LD50 (1 dose) was 7.3 ± 1.9 which indicated that on chronic administration captan was the most toxic of 12 drugs for which published values of the 100‐day LD50 index are available. Signs of toxicity were most evident during the first 3 weeks of daily administration and were due to a severe gastroenteritis, an inflammatory reaction in many organs, and degenerative changes in other organs.
The Toxicity of Two MAO Inhibitors Combined with 5‐HTP or L‐DOPA in Anaesthetized Mice
Authors: Männistö P. , Nikki P. , Rissanen A.
Published: July 2010

The combined toxicity of the MAO‐inhibitors phenelzine or pargyline + 5‐HTP or L‐DOPA was studied in conscious and halothane or pentobarbital anaesthetized mice. The rectal temperature of the mice was followed with a thermocouple. Halothane had a transient protective effect in phenelzine (60 mg/kg) + 5‐HTP (150 mg/kg) treated mice, whereas pentobarbital had no such effect. On the contrary, the toxicity was increased in pargyline (100 mg/kg) + 5‐HTP (150 mg/kg)‐treated mice anaestetized with halothane as compared with the toxicity in the unanaesthetized group. When L‐DOPA (300 mg/kg) was given together with phenelzine (60 mg/kg) or pargyline (100 mg/kg), the toxicity was decreased in the halothane anaesthetized and somewhat less decreased in the pentobarbital anaesthetized mice as compared with the unanaesthetized mice. The results suggest that halothane decreases the toxicity of MAO‐inhibitor + L‐DOPA through a central action, possibly by reducing the body temperature of mice during the critical period. The temporary protection in the halothane anaesthetized phenelzine + 5‐HTP group is probably due to the bronchodilation induced by halothane.
Metabolism of 1,1,1,2‐Tetrachloroethane in the Mouse
Authors: Yllner Sven
Published: July 2010

1,1,1,2‐tetrachloroethane was given subcutaneously to mice (1.2–2.0 g/kg) and the excretion was followed for 3 days. About half of the dose (21–62 %) was expired unchanged. The part metabolized was excreted mainly as trichloro‐ethanol (17–49 % of the dose), and to a lesser extent as trichloroacetic acid (1–7 %). The metabolites were identified by paper chromatography, gas chromatography and mass spectrometry and the Fujiwara reaction was used for the quantitative determination of trichloroacetic acid and of trichloroethanol after oxidation to this acid. It is suggested that the initial metabolic reaction is a hydrolytic fission of a carbon‐chlorine bond with the formation of trichloroethanol. Trichloroethanol was the precursor of trichloroacetic acid.
Metabolism of 1,1,2,2‐Tetrachloroethane‐14C in the Mouse
Authors: Yllner Sven
Published: July 2010

Labelled tetrachloroethane was synthesized by addition of chlorine to 14C‐acetylene. The product (0.51 μci/mg) was injected intraperitoneally into female albino mice (dose 0.21–0.32 g/kg) and the elimination of radioactivity was followed for 3 days. Half of the dose (45–61 %) was expired as carbon dioxide and 28 % (range 23–34) of the activity was excreted with the urine. About 16 % of the dose still remained in the animal and less than 4 % was expired unchanged. By paper chromatography and isotope dilution analysis, the urine was found to contain dichloroacetic acid, trichloroacetic acid, trichloroethanol, oxalic acid and small amounts of glyoxylic acid and urea. Half of the urinary activity was not accounted for. On simultaneous injection of benzoate considerable amounts of labelled hippuric acid, about 20 % of the dose, were excreted. It is suggested that the metabolism of tetrachloroethane takes place mainly via a stagewise hydrolytic fission of carbon‐chlorine bonds and oxidation to give first dichloroacetic acid and then glyoxylic acid. With part of the tetrachloroethane, a non‐enzymic dehydrochlorination occurs with the formation of trichloro‐ethylene which was also found in the breath. It is suggested that trichloroethylene is the precursor of the trichloroethanol and trichloroacetic acid found in urine.
Metabolism of14C‐Pentachlorophenol in the Mouse
Authors: Jakobson Inga , Yllner Sven
Published: July 2010

After subcutaneous or intraperitoneal injection of14C‐pentachloro‐phenol (14C‐PCP) in the mouse (specific activity 1.6 μci/mg, dose 15–37 mg/kg body weight) the distribution of the activity in the body was determined by whole‐body autoradiography and by analysis of the individual organs after oxidation to14CO2. The highest specific activity was found in the gall bladder and its contents, the wall of the stomach fundus, the contents of the gastro‐intestinal tract and the liver. This shows that there is both a gastric and a biliary secretion of PCP and/or its metabolites, and excretion in the faeces. Most of the activity (72–83 %) was excreted in the urine in four days, about half of the dose in 24 hours. Only traces (< 0.05 %) were detected in the expired air. Identification and estimation of metabolites were performed by paper chromatography and isotope dilution techniques. All the urinary activity in the first 24 hours was due to PCP and probably tetrachlorohydroquinone. At least PCP was excreted in both the free and the conjugated form.
Changes in the Formation of3H‐Catecholamines from3H‐DOPA and3H‐Tyrosine Induced by Unlabelled DOPA
Authors: Persson Torgny , Waldeck Bertil
Published: July 2010

Various doses of L‐DOPA were given intravenously to mice together with3H‐L‐DOPA or3H‐tyrosine. Two hours later the animals were killed. The3H‐noradrenaline (NA) and3H‐dopamine (DA) in the caudate nucleus, the remainder of the brain and the heart were determined. In some experiments only unlabelled L‐DOPA was given and NA and DA were determined fluorimetrically. With doses of DOPA 10 and 100 mg/kg, the3H‐NA but not the3H‐DA formed from3H‐DOPA in the brain decreased, indicating a saturation of the DA β‐hydroxylase. In the heart a similar decrease was observed with a ten times lower dose. In the caudate nucleus an increased synthesis of3H‐DA from3H‐DOPA was observed following the administration of 100 mg/kg DOPA. The formation of3H‐NA both from3H‐tyrosine and from3H‐DOPA was influenced in a similar way by DOPA. There were no marked changes in the levels of unlabelled amines under the present experimental conditions.
Effect of Some Sympathomimetic Amines on the Tissue Clearance of Radiosodium Injected into the Hind Leg of the Rat
Authors: Åström A. , Persson N. H.
Published: July 2010

The effect of some sympathomimetic amines on the rate of disappearance of22Na injected into the hind legs of rats was studied. The technique used was developed particularly for studying the influence of new drugs on capillary blood flow, i.e. the factor primarily determining drug absorption. Decreased capillary circulation (sodium clearance) in the muscle pocket of the sciatic nerve was produced, in order of efficacy, by adrenaline, noradrenaline, levonordefrin, phenylephrine and metaraminol, in concentrations of 10 and 100 μg/ml. Isoprenaline in low concentration (0.01 μg/ml) was found to enhance capillary circulation.
Biliary Excretion of Quaternary Ammonium Compounds and Tertiary Amines in the Rat
Authors: Ryrfeldt Åke , Hansson Eskil
Published: July 2010

The biliary excretion of some isotopically labelled quaternary ammonium compounds and tertiary amines have been studied in rats after intravenous administration. The elimination of radioactivity into the bile was followed 4–6 hours. The amount of radioactivity eliminated ranged from 0.0–54% of the given doses of activity. Chromatographic studies indicated that only a small fraction of the activity eliminated into the bile was attributable to the original compound in most of the cases in which extensive excretion of radioactivity was noted. Metabolites were formed which seemed to be more polar than the original compounds. Molecular properties for biliary excretion are discussed.
Effect of Tetraethylammonium and N1‐Methylnicotinamide on the Uptake of Decamethonium and Carbamoylcholine by Slices of Mouse Kidney
Authors: Holm Jan
Published: July 2010

An investigation was performed to determine whether decamethonium and carbamoylcholine share a common transport mechanism with tetraethyl‐ammonium and N1‐methylnicotinamide in mouse kidney slices. Slices were incubated (1 hour) in Krebs‐Ringer bicarbonate medium (37°, pH 7.4) containing 2 × 10‐6M14C‐labelled decamethonium or carbamoylcholine both in the absence and presence of the drugs. Tetraethylammonium and N1‐methylnicotinamide stimulated decamethonium uptake at relatively low concentrations (5 × 10‐5M and 10‐4M tetraethylammonium, 10‐4M and 5 × 10‐4M N1‐methylnicotinamide), whereas both agents at higher concentrations (10‐3M and 10‐2M tetraethylammonium, 2 × 10‐2M N1‐methylnicotinamide) depressed the uptake. Tetraethylammonium (10‐4M, 10‐3M) and N1‐methylnicotinamide (10‐3M) also inhibited the uptake of carbamoylcholine. The initial decamethonium influx (3 minutes incubation) could be stimulated by pre‐incubating slices (1 hour) with 3 × 10‐4M tetraethylammonium or 5 × 10‐4M N1‐methylnicotinamide (in the absence of decamethonium) before being transferred to a final medium containing only decamethonium. Stimulation can thus be interpreted as an example of accelerative exchange diffusion, which should indicate that efflux of tetraethylammonium or N1‐methylnicotinamide accumulated by the slices accelerates the influx of decamethonium. It is concluded that decamethonium and carbamoylcholine use a carrier mechanism which is also involved in tetraethylammonium and N1‐methylnicotinamide transport. This transport mechanism is most likely in part at least, identical with that responsible for the secretion of tetraethylammonium and N1‐methylnicotinamide (and other organic cations) by the intact kidney.
A Comparison between Phenol Red and51Cr‐EDTA as Reference Substances in Rats by a Test Meal Technique
Authors: Kristoffersen John , Lökken Per
Published: July 2010

In quantitative studies of gastric functions, calculations based on the recovery of an ideal non‐absorbable reference substance from the stomach allow corrections for the loss of the gastric contents through the pylorus. When the gastric contents of histamine stimulated rats were aspirated 45 minutes after oral administration of test meals at pH 6.5 containing phenol red or51Cr‐EDTA, the mean recovery of phenol red (37.0 % ± 1.4) was significantly lower than the corresponding value for51Cr‐EDTA (48.7% ± 2.2). Consequently, when the calculations were based on phenol red as a reference substance, significantly larger volumes of fluid and higher amounts of HCl were estimated to have passed through the pylorus. In a paired comparison with the two compounds given in the same test meal, similar results were obtained. Mucosal binding and absorption of phenol red are suggested as the most likely explanations for the discrepancy. In addition to high stability, inertness, and a more complete recovery, the water‐soluble51Cr‐EDTA complex offers analytical advantages. In the present method51Cr‐EDTA thus seems to meet the requirements of a satisfactory reference substance better than phenol red.
Studies on the Relationship between Morphine Analgesia and the Brain Catecholamines in Mice
Authors: Paalzow Lennart , Paalzow Gudrun
Published: July 2010

The catecholamine content in the mouse brain has been investigated after the administration of an analgesic dose of morphine. A single dose of 7.5 mg/kg produced a significant reduction in brain noradrenaline during a time‐period of maximal analgesic activity. After inhibition of the rate limiting step of catecholamine synthesis a decrease in noradrenaline content was still obtained. Now even a reduction was found in dopamine content, but this appeared later and was more short‐lasting than the change in noradrenaline. By investigating individual differences in analgesia among animals after inhibition of the catecholamine synthesis or inhibition of dopamine β‐hydroxylation respectively with disulfiram further support was obtained for the view that the release of noradrenaline by morphine is correlated with the analgesic activity better than do changes in dopamine. The possibility that morphine analgesia is induced by interference at the storage sites of brain noradrenaline is discussed.
The Difference in Methaemoglobin Formation by 6‐Amino Metabolites of DNOC and DNBP in Ruminant and Nonruminant Animals with Special Reference to Sheep and Swine
Authors: Fröslie Arne
Published: July 2010

The 6‐amino metabolites of the dinitrophenols DNOC and DNBP have been investigated for their methaemoglobin‐forming effect in sheep and swine. When given intraperitoneally, none of these metabolites had any effect in swine, while 6‐ANOC only, had a weak effect in sheep. In contrast, intraruminal administration of these metabolites, leads to significant methaemoglobinemia in sheep. At doses of 40 mg/kg 6‐ANOC had a moderate effect, while corresponding molar doses of 6‐ANBP had a severe toxic effect with considerable and longlasting methaemoglobinemia and haemolysis. After intraperitoneal administration of 6‐ANOC, the metabolite 6‐AcANOC was demonstrated in the plasma both in sheep and swine, while a corresponding acetylated derivative of 6‐ANBP was never detected. At least 95% of the aminophenols in the plasma were bound to the plasma proteins. The results are discussed in relation to the ruminal metabolism of DNOC and DNBP, and to the ruminants' special response to these substances. The diamino metabolites have been considered as the possible inducers of methaemoglobinemia following dinitrophenol poisoning in ruminants.
On the Distribution of Cadmium in Blood
Authors: Nordberg Gunnar F. , Piscator Magnus , Nordberg Monica
Published: July 2010

Cadmium in the blood has been considered to be bound to haemoglobin. In the blood of mice given repeated injections of CdCl2 (0.5 mg Cd/kg), however, more than 60 per cent of the cadmium was bound to a protein substance with low molecular weight (about 10,000), clearly separable from haemoglobin by G‐75 Sephadex chromatography. In other mice given repeated injections of 0.25 mg Cd/kg, about 25 per cent of blood‐cadmium was associated with this substance.
The Effect of Bendroflumethiazide (Centyl®) on the Renal Excretion of Calcium and Sodium in Normal, Parathyroidectomized, Thyroidectomized and Thyroparathyroidectomized Rats
Authors: Jørgensen Fritz Schønau
Published: July 2010

The effect of administration of bendroflumethiazide in supramaximal doses on calcium and sodium excretion in intact, parathyroidectomized (PX), thyroidectomized (TX) and thyroparathyroidectomized (TPX) rats has been investigated. In all the groups the thiazide compound causes reduction in renal calcium excretion. In intact rats but not in the PX, TX, or TPX groups, an increased urinary excretion of calcium is seen after cessation of thiazide administration. The calcium concentration in the serum is not changed during thiazide administration. No accumulation of calcium in the aortic, heart or muscle tissue can be detected during thiazide administration. The benzothiadiazine diazoxide (proglicem®) does not cause any change in renal calcium excretion. A change in the ratio of parathormone/calcitonin concentration appears to take place during thiazide administration.
The Physicochemical and Pharmacokinetic Bases for the Biopharmaceutical Evaluation of Drug Biological Availability in Pharmaceutical Formulations
Authors: Garrett Edward R.
Published: July 2010

Abstract:The operational determination of the bioavailability of a vital drug from its pharmaceutical formulation by the extent and rate of its appearance in the blood and tissues of an intact biological organism is termedbiopharmaceutics.Such bioavailability is a complex function of the physicochemical factors that determine its stability in the formulation and in the biological fluids; the rate of release of drug particles from, or disintegration of, the formulation matrix; the rate of dissolution of the dispersed drug particles as affected by the pH, volume, and agitation of the dissolution media; the solubility of the drug in the solvent; its transport to the absorption site; the pKa of the dissolved substance that determines the concentration of neutral species at the pH at the site; the partition of dissolved drug into the lipid‐like membranes and the subsequent rate of diffusion into the body compartments.Pharmacokineticsdetermines the amounts of drug absorbed, the rate of absorption and release from the pharmaceutical formulation in the intact biological system. Experimental data may be obtained from amounts of drug and/or metabolites monitored in the urine, faeces and blood as functions of time. Total amounts excreted and areas under blood level‐time curves with their defined limitations are one set of criteria of bioavailability. Rates of absorption, deduced from rates of change of blood level and excretion, form another set of criteria whose various limitations are also defined. Dissolution rate studies have limiteda priorivalue in predicting bioavailability but may be useful in quality control procedures when correlated with biopharmaceutical data. Although many mathematical functions may be operationally useful in characterizingin vitrodissolution rates of drugs from dosage forms, the most valid presentation of data is the percentage og drug released at various time intervals.