bluuebunny/crossref_metadata_2025 huggingface dataset:
The Biotransformation of Cyclophosphamide in Man: Influence of Prednisone
Authors: Faber O. K. , Mouridsen H. T. , Skovsted L.
Published: July 2010

The effect of corticosteroid on the rate of biotransformation of cyclophosphamide in man was studied. Two opposite effects could be demonstrated. The immediate effect consisted of an inhibition of the biotransformation probably due to the inhibition of the hepatic drug‐metabolizing enzymes whereas prolonged treatment with prednisone resulted in an increased rate of biotransformation of cyclophosphamide, probably due to the induction of the same enzyme system.
Tissue Distribution of 14C‐Rifampicin I. Whole Body Autoradiography of Albino Mice
Authors: Boman Gunnar
Published: July 2010

Abstract: Whole body autoradiography of albino mice 5, 20, 60 min., 4, 24 hrs and 4 days after a single intravenous injection of 14C‐rifampicin showed that rifampicin and/or its metabolites were rapidly distributed into most organs. As early as 5 min. after the injection, the lung, myocardium, brown fat, salivary glands, gastrointestinal mucosa, pancreas, kidney and liver showed higher uptake than the blood. A blood‐brain barrier was apparent. A very high uptake was initially observed in the liver. Most of the radioactivity had disappeared after 24 hrs, although slight activity was still seen in the liver and thyroid after 4 days. No other specific retention of toxicological interest was observed.
Comparison of Pharmacological Effects of Some Local Anaesthetic Agents when using Water and Lipid Emulsion as Injection Vehicles
Authors: Jeppsson Roland
Published: July 2010

Abstract:Emulsified soya bean oil has been used as a vehicle for dissolving the base form of four local anaesthetics, lidocaine, quatacaine, butacaine and benzocaine and these formulations have been injected subcutaneously and intravenously into mouse and cat. Pharmacological effects investigated were local anaesthesia, smooth muscle relaxation and anti‐arythmic effect. The magnitude of these effects were quantitatively compared when using the emulsion formulation and a water solution of the corresponding hydrochloride. Bothin vitroandin vivothe smooth muscle relaxation obtained when using the emulsion forms was smaller than with the water solutions, probably due to the fact that not all of the drug is immediately released from the oil phase. A moderate prolongation of the local anaesthetic effectsin vivoof lidocaine and quatacaine when administered subcutaneously into the mouse tail supports the assumption of a prolonged release of drug from the oil particles. Lidocaine in lipid emulsion given intravenously to cat protected the heart from electrical induced arythmias during a longer period of time than did the water solution. This response prolongation was explained by a combination of trapping of lipid particles in the myocardium and a slow release of the drug from the particles.
Effect of Stress on the Pharmacokinetics of Sodium Salicylate and Quinidine Sulphate in Rats *
Authors: Otto Uno , Paalzow Lennart
Published: July 2010

Abstract: Studies on the influence of foot shock stress on the absorption, distribution and overall serum elimination of sodium salicylate and quinidine sulphate were performed in rats. Foot shock stress was produced by grid floor electrical stimulation. The animals were stressed 1 hr before administration of the drugs and then throughout the experimental period. A significant induced stress was demonstrated by increased blood glucose levels and increased whole brain turnover of noradrenaline. Gastric emptying and intestinal transit as well as tissue levels of the drugs in the serum, heart, brain, liver, muscle and fat were determined. Results were obtained indicating that stress produced a significant increase in the gastro‐intestinal absorption of quinidine sulphate while no change in the distribution pattern or overall elimination was noted. On the other hand, sodium salicylate did not show any marked change in the pharmacokinetic parameters during a stressful situation.
Comparison of the Effect of Phenobarbital on the D‐Glucuronic Acid Pathway in Euthyroid and Hypothyroid Rats
Authors: Marselos Marios , Rantanen Tapio , Puhakainen Eino
Published: July 2010

Abstract: Hypothyroidism was produced in male rats by thiouracil (50 mg/kg daily, i. g., for 1 month), in order to study the thyroid control of the D‐glucuronic acid pathway in the liver. The activities of UDPglucose dehydrogenase, UDPglucuronosyltransferase, UDPglucuronic acid pyrophosphatase, D‐glucuronolactone dehydrogenase and 3‐hydroxyacid dehydrogenase were significantly enhanced by hypothyroidism. In contrast, β‐glucuronidase activity was decreased while that of L‐gulonolactone dehydrogenase was not affected. The excretion of L‐ascorbic acid in the urine was unchanged and that of D‐glucaric acid was decreased. Phenobarbital administration (80 mg/kg daily, intraperitoneally, for 3 days) induced UDPglucuronosyltransferase and D‐glucuronolactone dehydrogenase activities both in euthyroid and hypothyroid animals. The excretion of L‐ascorbic acid in the urine failed to rise after phenobarbital treatment in the hypothyroid state, although it increased in animals with normal thyroid function. D‐Glucaric acid excretion in the urine was increased by phenobarbital to the same extent in hypothyroid and euthyroid animals. The results suggest that hypothyroidism accelerates the flow through the D‐glucuronic acid pathway and perhaps that further metabolism of free D‐glucuronic acid takes place mainly via the L‐xylulose route, due to the highly increased activity of 3‐hydroxyacid dehydrogenase. Phenobarbital administration mainly brings about the same effects on both euthyroid and hypothyroid animals. The exception is the lack of increase in the urinary excretion of L‐ascorbic acid during hypothyroidism.
Effect of Methotrexate on Drug Absorption from the Rat Small Intestinein Situandin Vitro
Authors: Venho V. M. K.
Published: July 2010

AbstractThe effect of methotrexate (20 mg/kg intramuscularly) on the absorption of phenobarbitone, sulphafurazole, mecamylamine, quinidine and isoniazid from the rat small intestine was studiedin situandin vitro. The disappearance of all drugs studied from the intestinal fluidin situwas retarded on the third day after methotrexate administration. The fluid transfer and the amount of drugs passed through the intestinal wallin vitrowere also decreased. The absorption of phenobarbitone was reversible within six days, whereas the absorption of quinidine was still retarded on the sixth day after methotrexate administration. Methotrexate did not modify the amount of quinidine excreted into the intestinal lumen after intravenous administration. The levels of other drugs except isoniazid in the blood at the end of the experiment showed changes corresponding to their disappearance from the intestinal lumen.In situthe drug levels in the intestinal wall were much lower thanin vitro. Their levels in the intestinal wall reflected drug absorptionin vitrobut notin situ. The methotrexate‐induced reversible decrease in absorption seems to be attributable at least partly to diminished water flux through the intestinal wall, although other mechanisms may also exist.
Mobilization of Methyl Mercuryin Vivoandin Vitrousing N–acetyl–DL–penicillamine and other Complexing Agents
Authors: Aaseth Jan
Published: July 2010

AbstractThe distribution and excretion of mercury was studied in mice given a single intravenous dose of 5 umol/kg of methyl mercuric chloride. Oral treatment with N–acetyl–DL–penicillamine (3 mmol/kg per day) removed more mercury from the brain and from the whole body than the corresponding treatment with other complexing agents, and it was also effective on delayed treatment. Even more mercury was removed into the faeces and the urine, by higher doses of N–acetyl–DL–penicillamine, and 4 days of treatment with 27 mmol/kg per day of this compound did not give rise to any significant toxic symptoms in the mice.In vitroexperiments showed that the chemical affinity of N–acetyl–DL–penicillamine for methyl mercury was higher than that of the other thiols tested, except D–penicillamine. In contrast to the latter, N–acetyl–DL–penicillamine easily penetrated the cellular membranes, and therefore rapidly removed a substantial fraction of methyl mercury from the blood cells. It is assumed that N–acetyl–DL–penicillamine can reduce the mercury concentration in brain cells by converting the intracellularly non–diffusible methyl mercury into a freely diffusible complex.
The Effect of Nifedipine on the Effective Refractory Period and Excitability of the Isolated Rat Atrium at Different Calcium Levels and Frequencies of Stimulation
Authors: Refsum Helge , Landmark Knud
Published: July 2010

AbstractThe effect of calcium and a calcium–antagonistic drug, nifedipine, on the effective refractory period (E. R. P.) of electrically stimulated, isolated rat left atria was studied and compared with the effect on the duration of the intracellularly recorded action potential. To determine E. R. P., two different methods were used. When E. R. P. was determined from the maximum following frequency (m. f. f.), neither varying concentrations of calcium in the Ringer solution, [Ca++]o, nor nifedipine 100 μg/1 influenced E. R. P. significantly. However, when E. R. P. was measured by using programmed electrical stimulation, E. R. P. was shorter than when determined from m. f. f., increasing [Ca++]odecreased E. R. P. and nifedipine 100 μg/1 shortened E. R. P. at low [Ca++]o(2.0 meq./l). Increasing atrial rates also produced a decrease in E. R. P., and the shortening effect of nifedipine was enhanced by increasing the stimulus frequency. The electrical threshold for stimulation increased both with increasing [Ca++]oand increasing stimulus frequencies. However, nifedipine 100 μg/1 had no significant effect on the excitability. It is concluded that programmed electrical stimulation is a more accurate method than m. f. f. for determining E. R. P., and also that a correlation exists between the effect of calcium on E. R. P. and on the action potential duration.
The Metabolism of Biphenyl. III. Phenolic Metabolites in the Pig
Authors: Meyer Trygve , Larsen John Chr. , Hansen Ernst V. , Scheline Ronald R.
Published: July 2010

Abstract The phenolic metabolites of biphenyl in both male and female pigs were qualitatively and quantitatively analysed as trimethylsilyl (TMS) ethers by combined gas chromatography/mass spectrometry and gas chromatography, respectively. This xenobiotic was metabolized mainly to mono–hydroxylated biphenyl, and in small amounts to di– and tri–hydroxylated biphenyls. Urinary excretion was the only route of elimination of these compounds from the body. The total urinary recovery in male pigs was 44.8 % of the dose 96 hrs after administration of the drug, and the corresponding value in female pigs was 27.6%. The main part of the urinary metabolites was excreted during the first 24 hrs after dosing in both sexes.
The Foeto–Maternal Distribution of Digoxin in Early Human Pregnancy
Authors: Allonen Hannu , Kanto Jussi , Iisalo Esko
Published: July 2010

Abstract The concentrations of digoxin in maternal and foetal serum and in foetal tissues were measured after two oral doses in 12–16 weeks pregnancies. In maternal serum a digoxin level of 1.3 ng/ml was found, while the foetal serum level was 0.7 ng/ml. The placenta had a concentration of 5.8 ng/g, but no measurable amounts of digoxin were found in amniotic fluid, foetal heart, kidney, liver or muscle.
Effects on Rat Urinary Kallikrein Excretion of Bumetanide, Bendroflumethiazide and Hydralazine
Authors: Nielsen Chr. Kægaard , Arrigoni‐Martelli E.
Published: July 2010

Abstract Single and/or repeated administrations of bumetanide, bendroflumethiazide and hydralazine to normotensive and spontaneously hypertensive rats resulted in an increase of urinary kallikrein excretion. No correlation was found with sodium output. The role of the increased plasma renin activity is discussed and it is suggested that the activation of the renal kallikrein‐kinin system is related to the increase in renal blood flow.
Effect of a Vasopressin Analogue (Na‐glycyl‐gIycyl‐glycyI‐[8‐lysine]‐vasopressin) on Organ Blood Flow in the Pregnant Guinea Pig
Authors: Sjöquist P. O. B. , Bjellin L. , Carter A. M.
Published: July 2010

AbstractNa‐triglycyl‐(8‐lysine)‐vasopressin (TGLVP) was administered intravenously to pregnant guinea pigs and the effect on regional blood flow examined by the radioactive microsphere technique. A dose of 10 μg/kg TGLVP caused an elevation of the mean arterial blood pressure, from 6.4 to 11.1 kPa, a significant reduction in blood flow to the gut, skin and skeletal muscle and a significant increase in blood flow to the spleen. The number of 15 ± 5 urn microspheres reaching the lungs diminished significantly after 10 μg/kg TGLVP, indicating that this dose constricted arterio‐venous short circuits in the systemic circulation. There was also a decrease in blood flow to the urogenital tract, including the placentae. When 3 μg/kg TGLVP was injected, the mean arterial blood pressure rose from 6.5 to 8.7 kPa and there was no longer any consistent effect on maternal placental blood flow. It is suggested that pregnancy constitutes a contraindication for TGLVP, since a reduction in uterine and maternal placental blood flow might occur with clinically relevant doses.
The Effect of Phenytoin on the Tissue Concentrations of Digoxin in the Rat
Authors: Allonen Hannu
Published: July 2010

AbstractRats treated chronically with digoxin were treated with two different dose levels of phenytoin, either as a single dose or chronically. Digoxin concentrations were measured by radioimmunoassay in the serum, urine, heart, muscle, liver, and the kidney. Chronic treatment with the high dose of phenytoin significantly increased the digoxin levels in the serum and tissues and decreased the renal clearance of digoxin. The low dose of phenytoin significantly reduced the serum and tissue levels of digoxin and increased the renal clearance. Single doses of phenytoin had a tendency to cause similar changes. Levels of digoxin were altered during the phenytoin treatment. In contrast to man. digoxin is extensively metabolized in the rat. Enzyme induction in connection with low phenytoin dosage and inhibition by high dosage is the suggested mechanism. It can be speculated that the tissue distribution and excretion of digoxin are altered.
Differential Inhibition of Aryl Hydrocarbon Hydroxylase in Human Foetal Liver, Adrenal Gland and Placenta*
Authors: Pelkonen Olavi
Published: July 2010

AbstractIt is known from experiments on rats and mice that control and polycyclic aromatic hydrocarbon‐induced activities of aryl hydrocarbon hydroxylase differ profoundly with regard to their inhibition by several compounds. In order to obtain information about the nature of the human enzyme system from different tissues, the inhibition of aryl hydrocarbon hydroxylase (AHH) by different compounds in the human foetal and adult liver, foetal adrenal gland, as well as the placenta was studied. Substantial AHH activity was present in all the livers and adrenal glands, but only in term placentas from smoking mothers. The placental AHH was inhibited by 7,8‐benzoflavone, but not appreciably by SKF 525 A, aminopyrine or metyrapone. On the other hand, the foetal liver AHH was inhibited by SKF 525A, aminopyrine and metyrapone, whereas 7,8‐benzoflavone apparently activated the enzyme. The adult human liver AHH resembled that of foetal liver. The foetal adrenal AHH displayed a pattern of inhibition differing from both the liver and the placenta. Maternal cigarette smoking did not have a substantial effect either on the enzyme activity or on the inhibitory properties. Foetal hepatic AHH resembled the enzyme from control‐rat liver and the placental AHH was similar to the enzyme from 3‐methylcholanthrene‐treated rat liver. The effect of 7,8‐benzoflavone on control rat liver AHH activity varied greatly from the prenatal to the adult period, whereas AHH activity in MC‐treated rat liver was always strongly inhibited by 7,8‐benzoflavone.
Prostaglandin/Kinin Activity Related to Changed Renal Compliance after Bumetanide in Dogs
Authors: Olsen Uffe Bang
Published: July 2010

Abstract: Bumetanide (0.25 mg/kg intravenously) increases kidney volume by 20% at maximal diuresis in anaesthetized dogs. The kidney expansion is initially accompanied by a 2–4 fold increase in the subcapsular pressure, which is normalized at a time when kidney volume is still considerably increased. Renal blood flow and urinary kinin excretion are enhanced parallel to kidney volume. Renal prostaglandin E activity decreases. The increase in renal blood flow and urinary kinin excretion are inhibited by indomethacin pretreatment. The results leads to the conclusion that the kinins mediate the vascular response of bumetanide. The results also suggest that the subcapsular/interstitial pressure might affect the prostaglandin level of activity after bumetanide while factors related to tubular volume activate the kallikrein‐kinin system.
Effect of Propranolol and Related Drugs on Transmembraneous pH Differences in Liposomes
Authors: Åkerman Karl E. , Järvisalo Jorma O.
Published: July 2010

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

Abstract:The liver microsomal p‐hydroxylation of amphetamine to parahydroxyamphetamine (pOHA) was dependent on NADP and inhibited by carbon monoxide indicating the involvement of cytochrome P‐450. SKF 525‐A, fenfluramine and desmethylimipramine were the most effective inhibitors of this pathway of amphetamine metabolism. Repeated administration of phenobarbital resulted in reduced p‐hydroxylation of amphetaminein vitro. Chronic administration of amphetamine reduced the microsomal p‐hydroxylation of amphetamine without apparent changes in the cytochrome P‐450 levels or in the activity of NADPH‐cytochrome c reductase. The aromatic hydroxylation of aniline and the demethylation of ethylmorphine was not affected by this treatment. However, the 455 nm complex formed during the microsomal metabolism of N‐hydroxyamphetamine was increased by the long‐term administration of amphetamine. These results indicate some pecularities of thein vitrohydroxylation of amphetamine by rat liver microsomes. Amphetamine disappeared from the perfusate of the perfused liver at the same rate in rats given a single dose of amphetamine and in rats given amphetamine orally for four weeks. The excretion of pOHA and its conjugate increased at 60 and 90 min. and30, 60 and 90 min. respectively in the perfusate of the same experiment as compared to the controls. The total excretion of radioactive amphetamine metabolites at the end of the perfusion was increased in the perfusate and reduced in the bile compared to the control experiment.
Actions of a New Vasopressin Analogue (1‐deamino‐6‐carba‐[8‐arginine]‐vasopressin) on Regional Blood Flow in Pregnant Guinea Pigs
Authors: Sjöquist P.‐O. B. , Mårtensson L. , Bjellin L. , Carter A.M.
Published: July 2010

AbstractRegional blood flow responses to 1‐deamino‐6‐carba‐(8‐arginine)‐vasopressin (dCAVP) were investigated in pregnant guinea pigs by the radioactive microsphere technique. Intravenous injection of 0.1 μg/kg body weight caused a moderate rise in mean arterial blood pressure from 6.8 to 7.9 kPa, a significant reduction in tissue perfusion of the stomach, mammary gland, urinary bladder and vagina, and a significant increase in renal and cerebral blood flow. In a small number of animals given 1.0 μg/kg of dCAVP, which evoked a strong pressor response, it was also possible to demonstrate a reduction in cutaneous and pancreatic blood flow and an augmentation of adrenal blood flow. Uterine and maternal placental blood flow did not alter significantly following administration of this vasopressin analogue.
In Vivo Reversibility of the Jejunal Glucose and Cation Transport Alteration Caused by Intraluminal Surfactants in the Rat
Authors: Sund Reidar Bredo , Jacobsen Dagfinn Nome
Published: July 2010

Abstract Tied jejunal loops in anaesthetized rats were under standardized conditions pre‐exposed for 30 min. with Tyrode solution containing surfactants. 5, 20 or 150 min. after wash out of bulk surfactant, the loops were re‐instilled with Tyrode containing glucose at 5–15 mmol/l. Net glucose, sodium and potassium transport were studied for 15 min. by changes in intraluminal amounts, and compared with results obtained in control rats. The surfactants (mmol/l) tested were the anionics dioctylsulphosuccinate (5.6) and dodecylsulphate (8.5–17), the cationics cetrimonium bromide (2.1–4.1) and benzalkonium chloride (2.1), the nonionics Triton X100 (0.25%) and Lubrol WX (0.25–0.5%) plus cholic acid (4.9) and desoxycholic acid (1.3–2.5). In most cases, the glucose transport was normal or fairly normal after 150 min., most of the restoration taking place shortly after surfactant removal. However, Lubrol in particular caused more irreversible effects. Generally, the changes in net cation transport tended to be less easily reversible than the alteration in glucose transport. In so far as a normal or near to normal glucose transport is unlikely to occur unless both functional and structural integrity of the epithelium is preserved, the results indicate that in most cases there is but insignificant epithelial damage under the experimental conditions. Since, furthermore, these surfactants can interact with glucose transport in the same technique even at lower concentration and shorter incubation time than used here, it is concluded that the interaction of surfactants with intestinal transport is not neccessarily linked to gross histo‐pathological changes.
The Supraspinal Control of the Urinary Bladder
Authors: Carlsson Carl‐Axel
Published: July 2010

Abstract The supraspinal mechanisms involved in the control of micturition are reviewed on the basis of experimental data and clinical observations.
Verapamil and Nifedipine Inhibition of Contractions Induced by Potassium and Noradrenaline in Human Mesenteric Arteries and Veins
Authors: Mikkelsen E. , Andersson K.‐E. , Pedersen O. Lederballe
Published: July 2010

AbstractRing preparations of human mesenteric arteries and veins were contracted by noradrenaline (1.8×10‐5M) or potassium (127mM). Isometric tension was recorded. In the arterial preparations, the maximum response to noradrenaline was 97±8% (mean±S.E.M.) of that to potassium. In the veins, the corresponding figure was 38±4%. The calcium antagonists verapamil (2.2±10‐7‐2.2± 10‐5M) and nifedipine (2.9×10‐8‐2.9×10‐6M) relaxed both arteries and veins contracted by noradrenaline or potassium, and reduced the responses to these agents when added 15 min. before stimulation. The time course of relaxation of potassium contracted preparations, induced by verapamil and nifedipine, was more rapid and complete than that produced by a calcium‐free, high potassium solution. In contrast to verapamil, nifedipine caused a more pronounced inhibition of the potassium than of the noradrenaline evoked contractions in both arteries and veins. After exposure to a calcium‐free medium for 30 min., the arterial response to noradrenaline was significantly (P<0.05) greater than that to potassium. However, the reverse was found in the veins. In both types of vessel, verapamil (2.2×10‐6M) and nifedipine (2.9‐10‐7M) were equi‐effective in reducing the noradrenaline and potassium induced responses in calcium‐free medium. The results suggest that there are differences in reactivity, not only between mesenteric arteries and veins, but also between, e.g. peripheral and mesenteric vessels. The calcium antagonists nifedipine and verapamil do not have an identical mode of action. However, both agents seem to inhibit influx of extracellular calcium, and might also have an inhibitory effect on the release of intracellular calcium.
Inhibition of3H‐Dopamine Accumulation in Reserpinized and Normal Rat Striatum
Authors: Ross Svante B. , Kelder Diana
Published: July 2010

AbstractThe inhibitory potencies of 27 compounds on the accumulation of3H‐dopamine (DA) in synaptosome‐rich striatal homogenates of normal and reserpinized rats were determined. It was found that some compounds, e.g. amphetamine derivatives, phenmetrazine, phenethylamine derivatives and tryptamine derivatives were considerably more potent in the reserpinized preparation than in the normal one. Other compounds, e.g. amfonelic acid, mazindol, EXP 561, benztropine, pipradrol, nomifensine, methylphenidate and cocaine had similar potencies in the two preparations. It is suggested that the compounds enhanced by reserpine are more potent as DA releasing agents than as inhibitors of the DA uptake, whereas the compounds in the other group are most potent as uptake inhibitors. Interestingly, these two groups completely agree with the two groups of central stimulatory agents, viz. the amphetamine‐like and the methylphenidate‐like drugs.
Structural Requirements for Uptake into Serotoninergic Neurones
Authors: Ross Svante B. , Ask Anna‐Lena
Published: July 2010

Abstract Experiments were performed to examine whether non‐hydroxylated tryptamines and 4‐chloroamphetamine utilize the membrane 5‐hydroxytryptamine carrier to pass into serotoninergic neurones. The accumulation and deamination of 14C‐tryptamine by mouse brain slices or homogenates of rat hypothalamus were not inhibited by cocaine or norzimelidine, a selective inhibitor of the neuronal 5‐HT uptake. The prevention by α‐methyltryptamine (10 mg/kg, intraperitoneally), α‐ethyltryptamine (20 mg/kg intraperitoneally) and 4‐chloroamphetamine (20 mg/kg intraperitoneally) of the irreversible inhibition of monoamine oxidase by pheniprazine (2.5 mg/kg intraperitoneally) and clorgyline (5 mg/kg intraperitoneally) in serotoninergic synaptosomes from mouse brain was not antagonized by pretreatment of the animals with norzimelidine (20 mg/kg intraperitoneally). The partial preventing effect of α‐ethyl‐4‐methyl‐m‐tyramine (H 75/12) (2× 50 mg/kg intraperitoneally) was, on the other hand, antagonized by norzimelidine. These results do not support the hypothesis that non‐hydroxylated tryptamines and 4‐chloroamphetamine are transported by the 5‐HT carrier.
Studies on the Mechanism of Action of LS 1727, a Nitrosocarbamate of 19‐Nortestosterone
Authors: Hartley‐Asp Beryl , Wilkinson Ray , Venitt S. , Harrap K. R.
Published: July 2010

Abstract: LS 1727, a nitrosocarbamate of 19‐nortestosterone, was active against lymphoid, antimetabolite‐sensitive, cell lines in vitro especially L1210 and Ehrlich ascites tumour lines. It was less effective against alkylating agent‐sensitive lines such as the Walker 256 carcinosarcoma. These results suggested a possible antimetabolite mode of action but LS 1727 had no effect on deoxy‐ or ribonucleotide pool sizes in L1210 cells. Studies on macromolecular synthesis showed an early inhibition of DNA synthesis whilst RNA and protein synthesis continued for 24–48 hours. This was reminiscent of a classic alkylating agent‐like effect. In vivo studies with specific alkylating agent‐sensitive, or antimetabolite‐sensitive tumours showed no antitumour activity although significant inhibition of Ehrlich ascites tumour cell growth was observed at high doses. In vitro cytotoxicity studies showed LS 1727 to be inactivated in the presence of mouse, rat and dog liver supernatants. This would explain the poor antitumour effects in vivo compared with the in vitro observations. Because LS 1727 is a nitrosocarbamate its possible mutagenic activity was investigated. LS 1727 was highly mutagenic but this property was also lost in the presence of a rat liver microsomal fraction. Although an effective cytotoxic agent in vitro LS 1727 is only effective in vivo at toxic doses.
A Keyboard Data Collecting Device for Behavioural Recordings
Authors: Höglund A. U. , Hägglund J.‐E. , Meyerson B. J.
Published: July 2010

Abstract: A keyboard data collecting device which makes it possible to record the duration, frequency and latency of ten different forms of behaviour simultaneously via direct observation, is presented. The device is simple to operate and easily built even in laboratories without advanced electronic knowledge. It makes the handling of extensive amounts of data easy, since a punched tape output of ASCII‐coded data is available for rapid computer processing.
Effect of Serotonin Antagonists on the Dextran‐induced Anaphylactoid Reaction in the Rat
Authors: Berstad Jan
Published: July 2010

Abstract: Dextran injected intravenously into rats causes a rapid lowering of the extent of activation of factor XII and of the plasma levels of prekallikrein and plasminogen, and at the same time a profound fall in blood pressure. The effects on these dextran‐induced reactions of three serotonin antagonistic lysergic acid derivatives were studied in the rat: bromolysergic acid diethylamide (BOL 148), methysergide, and ergotamine. BOL 148 was found to be the only effective inhibitor of the blood pressure fall, possessing an inhibitory effect over the dose range 1.0–4.0 mg/kg intravenously. The finding supports the assumption that part of the dextran‐induced blood pressure fall is mediated by serotonin through D‐receptors. All three serotonin antagonists showed a serotonin‐like lowering effect on the activation of factor XII and on the level of prekallikrein in plasma (BOL 148 1.0–4.0 mg/kg; methysergide 0.10–0.60 mg/kg; ergotamine 0.10–0.60 mg/kg). The results with the serotonin antagonists alone and in combination with dextran provided evidence that the serotonin‐mediated part of the blood pressure fall can not be secondary to the effect of dextran on the plasma parameters assayed.
Biliary Excretion of Bisacodyl and Picosulphate in Man: Studies in Gallstone Patients after Biliary Tract Surgery
Authors: Sund Reidar Bredo , Roland Magne , Kristiansen Sidsel , Salvesen Bjarne
Published: July 2010

Abstract: Bisacodyl (=BIS) and picosulphate (=PICO) have been given perorally to postoperative gallstone patients, who have undergone biliary tract surgery with the insertion of an indwelling T‐tube. The doses corresponded to 7.7 mg of their common free diphenol desacetylbisacodyl (=DES). The bile was sampled in hourly fractions from the external limb of the T‐tube; these fractions were analysed by a modification of the HPLC method previously used to study biliary excretion in the rat. In the BIS‐patients (n=8), DES in conjugated form occurred in significant concentration already in the first fractions; peak excretion values equivalent to 4–8 μg DES/ml bile were reached in 2–5 hours. Unchanged BIS could not be detected, and the concentration levels of unconjugated DES were insignificant. The PICO‐patients (n=8) on the other hand showed low DES concentrations (conjugated+free≤0.5 μg DES/ml) in all fractions, or low initial concentrations followed by a more or less pronounced rise in the later fractions. These results are, qualitatively, as in the rat. However, the dose fractions excreted in bile (assuming a total hepatic output of 50 ml/hour) seem smaller than those to be expected from rat experiments, at least as far as BIS is concerned.
Coronary Vasodilatory, Spasmolytic and cAMP‐Phosphodiesterase Inhibitory Properties of Dihydropyranocoumarins and Dihydrofuranocoumarins
Authors: Thastrup Ole , Fjalland Bjarne , Lemmich John
Published: July 2010

Abstract: Twentythree dihydropyrano‐ and dihydrofuranocoumarins, most of plant origin, were examined for their effects on the coronary flow of isolated perfused guinea‐pig heart, on the Ba2+‐induced spasms in isolated guinea‐pig ileum, on the cAMP level in guinea‐pig heart homogenate and on the cAMP metabolising activity of purified beef heart cAMP‐phosphodiesterase. For certain esters of dihydropyranocoumarin‐ and dihydro‐furanocoumarin alcohols coronary vasodilatory and spasmolytic activities comparable to those of papaverine were observed. A very close correlation between the coronary vasodilatory and the spasmolytic activity was found. The most potent structures maximally increased the cAMP level from 19 pmol/mg protein to about 60 pmol/mg protein and inhibited the cAMP‐phosphodiesterase activity with about 90%. The potencies were comparable to those of papaverine. A significant correlation was obtained between the coronary vasodilatory and the cAMP‐phosphodiesterase inhibitory activity. The results indicate involvement of cAMP‐phosphodiesterase inhibition in coronary vasodilatory effects of acyloxydihydropyrano‐ and acyloxydihydrofurano‐coumarins.
Interactions between Ethanol and Acetylsalicylic Acid in Damaging the Rat Gastric Mucosa
Authors: Puurunen Juhani , Huttunen Pirkko , Hirvonen Jorma
Published: July 2010

Abstract:The interactions between ethanol (EtOH) and acetylsalicylic acid (ASA) in damaging the gastric mucosa were investigated in urethane‐anaesthetised rats upon intragastric irrigation. The addition of 5, 10 or 20 mM ASA to 1 and 4 M EtOH instillates strongly aggravated lesion formation in the gastric mucosa and mucosal bleeding. ASA enhanced the back‐diffusion of hydrogen ions into the mucosa induced by 1 M EtOH, whereas gastric mucosal blood flow, which is thought to dispose of the back‐diffused acid from the mucosa, remained unchanged, thus resulting in an accumulation of acid within the gastric mucosa. ASA did not further enhance the strongly increased back‐diffusion of hydrogen ions induced by 4 M EtOH, but it effectively inhibited EtOH‐induced stimulation of the gastric mucosal blood flow, thus causing an increase in the ratio between hydrogen ion back‐diffusion and gastric mucosal blood flow. The simultaneous presence of EtOH and ASA did not enhance the rates of absorption of each from the instillates. The results indicate that EtOH and ASA have a strong synergistic action in damaging the gastric mucosa in the rat. The mechanism of this interaction may be an increased accumulation of hydrogen ions within the gastric mucosa, resulting in excessive acidification of the mucosal tissue.
Effect of Ethanol on the Pharmacokinetics of Penicillin in the Rat
Authors: Kourtopoulos Harry , Bolander Hans , Holm S. E. , Wahlström Göran
Published: July 2010

Abstract:The effect of a single intraperitoneal dose of ethanol (2 g/kg) given 30. min. prior to intravenous administration of benzylpenicillin (20, 40 and 80 mg/kg) was studied in rats. Ethanol pretreated animals showed lower blood and brain tissue levels of penicillin, 15 and 30 min. after the administration of the two lower penicillin doses. This difference was not observed when the penicillin dose was raised to 80 mg/kg. The quotient between brain and serum concentrations was increased 45 min. after the injection of 20 mg/kg of penicillin. Urine collection during the following 2 days showed an increased urine volume during the first 4‐hour period in animals pretreated with ethanol. During the same time period they excreted less benzylpenicillin than the controls.
Drinking Water and Drug Dosage in Rat Studies
Authors: Jespersen Lennard Tang , Pedersen O. Lederballe , Mikkelsen E. O. , Jakobsen P.
Published: July 2010

Abstract: Spontaneously hypertensive rats were treated with verapamil, hydralazine, indapamide or bepridil added to their drinking water. These substances had most different effects on the water consumption of the animals, displaying both positive and negative feed‐back mechanisms. Furthermore there were considerable differences in stability of the drugs in solution. It is therefore concluded that continuous control of water intake and analysis of the stability of the drug is essential for the establishment of proper dose‐response relationships.
Fenflumizole: Interactions with the Arachidonic Acid Cascade
Authors: Corell Tim , Hasselmann Gert , Splawinski Jacek , Wojtaszek Barbara
Published: July 2010

Abstract: Fenflumizole (2‐(2,4‐difluorophenyl)‐4,5‐bis(4‐methoxyphenyl)imidazole), a new non‐steroidal antiinflammatory agent, was investigated for interference with cyclo‐oxygenase activity in vivo, ex vivo and in vitro in comparison with indomethacin (and aspirin). Fenflumizole was comparable to indomethacin ex vivo in inhibition of thromboxane (TX)A2 production in rabbit platelets and inhibition of prostaglandin (PG)I2 (∼prostacyclin) generation in rabbit mesenteric arteries and in vivo as an inhibitor of PGE2 formation in inflammatory exudates in rats. Fenflumizole was 18 times less active than indomethacin in inhibition of PGE2 synthesis in vitro and 170 times weaker as an inhibitor of PGI2 generation in the rat stomach mucosa ex vivo. Fenflumizole was 20–50 times more potent than indomethacin in vivo in inhibition of arachidonic acid induced bronchoconstriction in guinea‐pigs, in inhibition of platelet aggregation on tendons superfused with blood from rabbits and in vitro in inhibition of aggregation of human and rabbit platelets. Neither fenflumizole nor indomethacin inhibited TXA2‐synthetase in vitro. Aspirin – when tested – was less potent than fenflumizole and indomethacin. It is concluded that fenflumizole is a potent cyclo‐oxygenase inhibitor. The very potent activity of fenflumizole against platelet aggregation and bronchoconstriction suggests a selectivity in the mode of action. The weak inhibition of gastric PGI2 generation may account for the previously observed weak gastro‐ulcerogenicity of fenflumizole.
Streptozotocin‐induced Impairment of Islet B‐Cell Metabolism and its Prevention by a Hydroxyl Radical Scavenger and Inhibitors of Poly(ADP‐ribose) synthetase
Authors: Sandler Stellan , Welsh Michael , Andersson Arne
Published: July 2010

Abstract: The possible protective effects in vitro of the hydroxyl radical scavenger dimethyl urea (6 mg/ml) and the poly(ADP‐ribose)synthetase inhibitors theophylline (5 mM) and nicotinamide (0.75 mg/ml) against streptozotocin (SZ) induced deterioration of islet metabolism were investigated using isolated mouse pancreatic islets. All these compounds counteracted to different extents the deleterious effects of SZ (4.4 mM) on glucose‐stimulated (pro)insulin biosynthesis, dimethyl urea protecting least. No protective effects against SZ were obtained by adding 16.7 mM glucose or 5 mM dibuturyl cAMP. The islet NADH+NAD content decreased drastically when exposed to SZ. Again, nicotinamide and theophylline protected better against the SZ‐effects on pyridine nucleotides than dimethyl urea. Furthermore, the maintenance of a linear rate of oxygen uptake was lost after SZ‐exposure of the islets, and there was no increase of the respiratory rate when these islets were challenged with high glucose. Also in these islet respiratory studies a partial or total protection by dimethyl urea, theophylline and nicotinamide against SZ was observed. In perifusion experiments SZ rapidly decreased insulin release together with a slightly delayed increased radioactive nucleotide efflux. Later (about 20 min.) a massive leakage of both radioactive nucleotides and insulin occurred in most of the experiments. It is concluded that all the observed impairments of islet metabolism after SZ‐exposure can be related to islet NAD depletion, which may depend on poly(ADP‐ribose)synthetase activation due to DNA damage. The SZ‐induced DNA injury may be mediated by free radicals as suggested by the protective effects of dimethyl urea.
Effect of Ethanol and pH on the Adsorption of Drugs to Activated Charcoal: Studiesin Vitroand in Man
Authors: Neuvonen Pertti J. , Olkkola Klaus T. , Alanen Tuija
Published: July 2010

Abstract:The effect of ethanol on the adsorption of aspirin, quinidine and amitriptyline to activated charcoal was studiedin vitroat pH 1.2 and 7.0. The adsorption of these drugs was greatly dependent on the charcoal‐drug ratio and on the pH. Ethanol (10%) significantly (P<0.001) increased the percentage of their unadsorbed fraction at both pHsin vitro.In six healthy volunteers activated charcoal (50 g), ingested 5 min. after aspirin (1000 mg) and quinidine sulfate (200 mg), reduced their bioavailability by about 70% (aspirin) and 99% (quinidine). A significant desorption of aspirin but not that of quinidine from charcoal was obvious on the second and third days and seemed to be related to the effect of pH. The absorption of ethanol was not significantly prevented by charcoal. The concomitant ingestion of alcohol (50 g) with drugs antagonized only slightly the ability of charcoal to reduce the absorption of aspirin and quinidine.
N‐Acetylpenicillamine Potentiation of Biliary Excretion of Methyl Mercury: Influence of Glutathione Depletors
Authors: Refsvik Tor
Published: July 2010

Abstract: The effect of I‐chloro‐2,4‐dinitrobenzene (DNB), sulfobromophtalein (BSP) and cyclohexene oxide (cho) on N‐acetylpenicillamine (NAPA) potentiated biliary excretion of methyl mercury in rats pretreated with cho for liver glutathione (GSH) depletion, has been tested. DNB, BSP and cho depressed NAPA potentiation of methyl mercury excretion in bile, while simultaneously biliary sulfhydryl concentration increased, due mainly to a relatively large proportion of unchanged NAPA, being excreted in bile. The fact that relatively large amounts of unchanged NAPA are excreted in bile, without affecting mercury excretion, indicates that NAPA per se cannot carry methyl mercury from liver to bile. In addition to unchanged NAPA, bile collected after administration of NAPA and DNB or BSP contained relatively large amounts of GSH conjugates of DNB or BSP, respectively, together with smaller amounts of GSH and another methyl mercury carrying component. The data are interpreted as suggesting that NAPA potentiation of methyl mercury excretion in bile can be due to an increased availability of GSH. However, it cannot be excluded that methyl mercury carrying components other than GSH and NAPA appearing in bile upon NAPA administration could play a role in NAPA potentiation of methyl mercury excretion in bile.
Potent Bronchodilating Effects of Enprofylline and Theophylline on Contractions Induced by Egg Albumin or by Slow Reacting Substance (SRS)
Authors: Hedman Susan E. , Andersson Rolf G. G.
Published: July 2010

Abstract: Isolated sensitized guinea pig tracheal smooth muscle tone was induced by use of egg albumin or SRS‐A (slow reacting substance of anaphylaxis). The dose‐response relationships of theophylline and enprofylline were studied on these preparations. Enprofylline was more potent than theophylline in relaxing the egg albumin‐ or SRS‐A‐induced tracheal muscle tone. The theophylline relaxation‐curve was significantly shifted to the left after addition of adenosine‐deaminase to the egg albumin‐contracted trachea, but this was not observed with the enprofylline relaxation‐curve. In SRS‐A‐contracted tracheas, the addition of adenosine‐deaminase did not significantly alter the relaxation curves of theophylline or enprofylline. It is therefore suggested that the relaxing effects of theophylline and enprofylline on SRS‐A‐induced contractions, at the therapeutically relevant concentrations demonstrated in this study, might be of importance for the antiasthmatic effects of xanthines.
Organ and Cellular Distribution of Inhaled Metallic Mercury in the Rat and Marmoset Monkey (Callithrix jacchus): Influence of Ethyl Alcohol Pretreatment
Authors: Khayat Amir , Dencker Lennart
Published: July 2010

Abstract:Distribution of inhaled radioactive metallic mercury vapour (203Hg0) in rats and Marmoset monkeys (Callithrix jacchus), with or without pretreatment by ethyl alcohol or aminotriazole (rat), was studied by means of whole‐body autoradiography, microautoradiography and scintillation counting of excised organs. Metallic mercury is oxidized by the catalase‐H2O2complex (Complex I) to the ionic form (Hg2+) and is known to be accumulated and retained in organs such as lungs, liver, myocardium, and brain, apparently after local oxidation in these organs. To this list of organs can be added the whole respiratory tract (nasal mucosa, trachea, and bronchi), a number of endocrine organs such as adrenal cortex, thyroid, corpora lutea of the ovaries, and interstitial tissues of the testes, the uvea and retina of the eye, and the salivary glands. In the liver, a regionalized pattern of distribution corresponding to the periportal hepatocytes was observed. Similarly, the subcapsular parts of the adrenal cortex (mainly the zona glomerulosa) were responsible for most of the adrenal mercury oxidation and retention. These organs (liver, adrenal) thus have a reserve capacity to oxidize Hg°. This is apparent also by the fact that ethyl alcohol and aminotriazole (known catalase inhibitors) — which depress oxidation and retention in most organs and whole body and thus increase blood concentrations of Hg°— cause an increased retention in most liver and adrenal cells.
Problems with potassium and magnesium in diuretic‐treated patients
Authors: Wester Per O. , Dyckner Thomas
Published: July 2010

Abstract:Teatment with thiazides and loop diuretics increase the urinary excretion of potassium and magnesium and the body content of these ions are reduced after long‐term treatment. The diuretic‐Miduced magnesium deficiency influences the potassium metabolism. Magnesium is a necessary activator of Na‐K‐ATPase, which supplies the Na‐K pump with energy. Lack of magnesium will therefore impair the pumping of sodium out of the cell and of potassium into the cell. The change of the relationship between extra and intracellular potassium may induce cardiac arrhythmias. Certain groups of patients, such as patients on digitalis therapy. patients with secondary hyperaldosteronism, eldcily patients with insufficient dietary habits, and heavy drinkers, run an additional risk of developing potassium/magnesium disturbances. In young patients with uncomplicated essential hypertension, the risk is probably very small.
Magnesium deficiency in congestive heart failure
Authors: Dyckner Thomas , Wester Per O.
Published: July 2010

Abstract: In congestive heart failure several compensatory mechanisms are operating, and may cause severe disturbances of both the internal and external electrolyte balance. The medical treatment prescribed in congestive heart failure also leads to changes in the handling of electrolytes. These combined effects may prove critical to the patient, especially with regard to the emergence of cardiac arrhythmias.