bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased Plasma Binding and Decreased Blood Cell Binding of Quinidine in Blood from Anuric Rats
Authors: Fremstad Dag
Published: July 2010

AbstractThe blood cell/plasma concentration ratio of quinidine, as influenced by the plasma protein binding, was studied in normal and anuric rats by applying incubation and equilibrium dialysis techniques on blood and plasma, respectively, from normal and anuric rats. The plasma protein binding of quinidine in anuria was increased at concentrations of unbound drug of less than 1.75 × 10‐4M and decreased above this concentration. At an assumed “therapeutic” quinidine concentration (1 × 10‐5M), the mean concentration ratio (total quinidine in blood cells)/(total quinidine in plasma) was 1.84 in normals and 0.46 in anuria, and the mean ratio (total quinidine in blood cells)/(unbound in plasma) was 4.45 and 1.81, respectively. As the latter ratios were concentration dependent and greater than could be accounted for by pH‐dependent distribution, quinidine is presumably bound in/on the blood cells. Reduced distribution ratio in anuria, even when related to unbound quinidine in plasma, also indicates changed binding in blood cells, a finding confirmed by applying the data to modified Scatchard plot. This may have implication for the use of blood cell/plasma concentration ratio as screening procedure for the altered plasma binding of quinidine in patients.
Guanethidine Induced Sympathectomy in the Adult Rat. II. Functional Effects Following Chronic Administration
Authors: Nielsen Gunnar Damgård
Published: July 2010

AbstractGuanethidine sulphate in doses of 5 and 40 mg/kg was administered intraperitoneally to adult rats daily for three months followed by discontinuation of administration for one day or three months. Following guanethidine 40 mg/kg a loss of approximately 95 % of the nerve cells of the superior cervical ganglion was observed. No changes were observed after 5 mg/kg. The average mean arterial blood pressure (measured under chloralose‐urethane anaesthesia) was lowered by 33 and 54 mmHg by guanethidine 40 mg/kg for three months followed by discontinuation for one day and three months respectively. The heart rate was unchanged. Guanethidine 5 mg/kg did not change any of these parameters. The increase in blood pressure and heart rate caused by intravenously administered noradrenaline was greatly enhanced following guanethidine 40 mg/kg, whereas only small changes were observed following 5 mg/kg. Following discontinuation for one day of 40 mg/kg for three months the potency ratios for the mean arterial blood pressure and the mean heart rate were 31 and 21 respectively, after discontinuation for three months 44 and 17 respectively. The potency ratios following guanethidine 5 mg/kg were 1.5 to 2.0. No changes were observed in the weight of the suprarenal glands following guanethidine. The present investigation has demonstrated an almost total chemical sympathectomy by guanethidine 40 mg/kg for three months and a persistent hypersensitivity to noradrenaline even after discontinuation of medication for three months.
Distribution and Fate of the Insect Repellent 14C‐N, N‐diethyl‐m‐toluamide in the Animal Body. II. Distribution and Excretion after Cutaneous Application
Authors: Blomquist Lars , Thorsell Walborg
Published: July 2010

Abstract The tissue distribution of 14C‐labelled N,N‐diethyl‐m‐toluamide (DEET), a widely used mosquito repellent, was studied by means of whole‐body auto‐radiography after cutaneous application to mice. The early picture was very similar to that previously observed after intravenous injection of the substance, with high concentration of radioactivity mainly in the lacrimal gland, liver, bile, intestinal contents, kidney, urine, and nasal mucosa. Urinary excretion in mice was highest early after application whereas in a human volunteer maximal excretion appeared only after several hours. In mice a low but significant excretion persisted throughout the observation time of one month, probably emanating from the considerable amount of radioactivity remaining in the smeared skin area, as observed both autoradiographically and by means of quantitative measurements.
Inducible Aldehyde Dehydrogenases in the Hepatic Cytosol of the Rat
Authors: Törrönen Riitta , Nousiainen Unto , Marselos Marios
Published: July 2010

Abstract Rats of the Wistar/Af/Han/Mol/(Han 67) strain have previously been shown to respond in a variable way to phenobarbital treatment, as far as the induction of aldehyde dehydrogenase activity is concerned (Marselos 1976). This biochemical property is genetically determined and concerns the high‐Km aldehyde dehydrogenase of the hepatic cytosol. In this study, administration of phenobarbital (1 mg/ml of drinking water, for 1 week) produces a uniform induction of aldehyde dehydrogenase in all rats, when measured with micromolar substrate concentration. The inducible low‐Km enzyme of the cytosol is not genetically determined like the high‐Km enzyme, and shows a wide specificity for aliphatic as well as for aromatic aldehydes. Despite the inducibility of the cytosolic enzymes, no alterations are found in the mitochondrial aldehyde dehydrogenase activities after phenobarbital treatment. The oxidation of D‐glucuronolactone takes place only in the cytosol, and seems to be dependent on the low‐Km aldehyde dehydrogenase. This is consistent with NMR studies, which showed that a very minimal amount of D‐glucuronolactone is in aldehyde form under the measurement conditions usually applied. Further, the oxidation of D‐glucuronolactone is also enhanced by phenobarbital in all rats without a genetic predisposition, and its dose‐response curve is very similar to that of the low‐Km aldehyde dehydrogenase.
Studies on the Duration of Local Anaesthesia: Structure/Activity Relationships in a Series of Homologous Local Anaesthetics
Authors: Åberg G. , Dhunér K‐G. , Sydnes G.
Published: July 2010

AbstractWhen the number of carbon atoms on the piperidine‐nitrogen of the mepivacaine molecule was increased up to four or five carbons, the toxicity of the compounds and the duration of their local anaesthetic effects were increased. With longer N‐alkyl‐chains, the general toxicity and the local anaesthetic potency ‐ but not the tissue toxicity ‐ were reduced. In dental infiltration anaesthesia only the short‐chain compounds offered an acceptable local anaesthesia. In these tests, the medium‐chain compounds had a very unfavourable quotient between dental anaesthesia and soft tissue anaesthesia, while the long‐chain compounds could not be tested at all in man because of their tissue irritating properties.
Effect of Piflutixol on Turnover of Catecholamines in Mouse Brain and Rat Corpus Striatum
Authors: Hyttel John
Published: July 2010

AbstractDopamine metabolismin vivowas studied after treatment with piflutixol (6‐fluoro‐9‐[3‐(4‐(2‐hydroxyethyl)piperidino)propylidene]‐2‐trifluoromethyl‐thioxanthene) a novel thioxanthene derivative with potent neuroleptic properties and sedative effects. In mice piflutixol increased both noradrenaline (NA) and dopamine (DA) turnover rate measured as increased disappearance of14C‐amines formed from14C‐L‐tyrosine. The ratio between the minimal effective doses for14C‐NA and14C‐DA disappearance was 2, which is of the same order of magnitude as obtained with cis(Z)‐chlorprothixene, pimozide and chlorpromazine. After14C‐L‐tyrosine the accumulation of14C‐dopamine was initially increased after which it decreased from day 4‐5. These changes resemble those obtained after other neuroleptics and parallel the initial receptor blockade and the subsequent receptor supersensitivity found in pharmacological experiments (MøllerNielsenet al.1977). Piflutixol induced a rapid increase in both DOPAC and HVA with a maximal effect after 2‐6 hours. After 2‐3 days the levels had returned to normal. The doses of piflutixol which at 24 hours doubled the levels of DOPAC and HVA were found to be 0.055 and 0.021 mg/kg subcutaneously, respectively. It is concluded that piflutixol is a powerful and long lasting DA receptor blocking agent, which changes the synthesis and release of DA in a way similar to basic neuroleptics.
Variations in the Blood Concentration of 1,1,2‐Trichloroethane by Percutaneous Absorption and Other Routes of Administration in the Guinea Pig
Authors: Jakobson Inga , Holmberg Bo , Wahlberg Jan E.
Published: July 2010

Abstract The blood concentration of 1,1,2‐trichloroethane was studied after epicutaneous application, by an intracutaneous, subcutaneous or intraperitoneal injection. An equation with three exponential terms was necessary for a satisfactory description of the experimental data in the case of intraperitoneal injection. Subcutaneous and intracutaneous injections seem to give essentially the same kind of blood concentration curves as for intraperitoneal injection. In the case of percutaneous absorption an equation with three exponential terms and a constant was necessary to account for the experimental data. The complex toxicokinetics of 1,1,2‐trichloroethane by percutaneous absorption was assumed to be associated with progressive skin damage observed in previously reported experiments, a damage apparently involving a change in barrier function.
Substituted Amphetamine Derivatives. II. Behavioural Effects in Mice Related to Monoaminergic Neurones
Authors: Ögren Sven‐Ove , Ross Svante B.
Published: July 2010

AbstractThe effects of the amphetamine derivatives (±)‐amphetamine (A), 2‐, 3‐ and 4‐chloroamphetamine (CA), 4‐methylamphetamine (MA) and chlorphentermine (CP) in producing central stimulation (increase in motor activity), antagonism of the reseipine syndrome, potentiation of 1‐dopa and 5‐hydroxy‐tryptophan (5HTP) responses in mice were investigated. The inhibitors of the membrane amine uptake desipramine (DMI) and chlorimipramine (CI) were also included in the study. It was found that the order in central stimulating potency was A > 3‐CA = 4‐CA > MA > CP. 2‐CA, DMI and CI decreased the motor activity. All the compounds potentiated the 1‐dopa response with the order of activity: 4‐MA > A > 2‐CA = 3‐CA = 4‐CA = CI ≥ DMI > CP. The decrease in motor activity (sedation) produced by reserpine was only reversed by A ≥ 3‐CA > 2‐CA. α‐Methyltyrosine but not parachlorophenyl‐alanine, antagonized the reversal effect. Three of the compounds (3‐CA, 4‐CA and MA) produced head‐twitches in the reserpinized mice. The 5‐HTP syndrome was potentiated in order of potency by MA = 4‐CA > CI > CP > 3‐CA whereas A, 2‐CA and DMI had no effect.
Effect of a Vasopressin Analogue (Nα‐glycyl‐glycyl‐glycyl‐[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

Abstract:Nα‐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 μm 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.
Plasma Levels and Electrophysiological Effects of Acebutolol (M & B 17.803) in the Dog Heartin Situ
Authors: Amlle Jan P. , Lcssum Steen , Collins Raymond F. , Landmark Knud
Published: July 2010

Abstract:The effect of acebutolol a β‐adrenergic receptor blocking agent was tested on the dog heartin situ. The drug decreased heart rate, and caused a reduction in the conduction velocity and a significant increase in the functional refractory period of the atrioventricular node. The functional and the effective refractory period of the right atrium was increased by acebutolol. During sinus rhythm, the drug did not affect conduction velocity in the rest of the conduction pathway. During atrial pacing, however, the intra‐atrial and His‐Purkinje conduction times were slightly increased. The plasma concentrations of acebutolol were in the range between 0.09 and 0.5 μg/ml, which is far below those values expected to cause a membrane‐stabilizing or quinidine‐like effect. The clinical applications of the results are discussed.
The Effect of Calcium and Beat Interval on the Contractile Force and Refractoriness of the Isolated Rat Atrium in the Absence and Presence of Nifedipine: A Possible Mechanism for the Negative Staircase Phenomenon
Authors: Landmark Knud , Refsum Helge
Published: July 2010

Abstract:An increase in the calcium concentration of the Ringer solution increased the contractile force and reduced the effective refractory period of the isolated rat left atrium paced at a frequency of 60 per min. An increase in the frequency of stimulation decreased the contractile force (negative staircase) and reduced the effective refractory period; these effects being most pronounced at the highest calcium levels. A calcium‐antagonistic drug, nifedipine, decreased the contractile force and the effective refractory period. The effect of an increased frequency of stimulation on the contractile force at different calcium levels in the absence and presence of nifedipine paralleled its effect on the effective refractory period. This observation suggests that both these phenomena are caused by a decreased quantity of inflowing calcium ions during the period of excitation, and thus might explain the absence of positive staircase in the rat myocardium.
Inotropic Action and Myocardial Uptake of Digoxin and Betamethyldigoxin in Isolated Guinea Pig Atria
Authors: Allonen Hannu , Iisalo Esko , Kanto Jussi , Pihlajamäki Kalevi
Published: July 2010

Abstract:The chronotropic and inotropic effects as well as the tissue levels of digoxin and methyldigoxin were studied in isolated guinea pig atria. Higher concentrations of methyldigoxin than of digoxin were required to cause arrhythmias. The inotropic potencies of the two glycosides did not differ from each another in equimolar concentrations in the organ bath. The increase in contractility correlated with the level of the glycoside in the organ bath and in the tissue. Digoxin was more effectively taken up by the heart tissue than methyldigoxin. Thus, when the tissue levels of the glycosides were the same, the contractility was greater after methyldigoxin than after digoxin.
Determination of the Vacant Amount of High‐Affinity Bilirubin Binding Site on Serum Albumin
Authors: Brodersen R.
Published: July 2010

Abstract A principle for determination of the vacant amount of the high‐affinity bilirubin binding site on serum albumin in the newborn is proposed: A small amount of monoacetyl‐4,4′‐diaminodiphenylsulphone (MADDS) is added to the serum sample and the equilibrium of binding of this substance is assessed by measuring the rate of dialysis into another volume of the same serum. It is shown that MADDS is bound selectively to the specific bilirubin site. Results obtained after addition of varying amounts of five drugs and of oleate are compared with those found by the peroxidase method. Good agreement is found although certain deviations are encountered, as expected in the case of allosteric affects. Free bilirubin concentrations can be calculated from the results.
In VivoInhibition of Prostaglandin Synthesis in Rabbit Kidney by Non‐Steroidal Anti‐Inflammatory Drugs
Authors: Oliw Ernst , Lundén Inger , Änggård Erik
Published: July 2010

AbstractTo define dose‐ and time‐response properties forin vivoinhibition of renal prostaglandin (PG) synthesis, aspirin, diclofenac sodium, indomethacin and d‐naproxen were injected intravenously in different doses to unanaesthetized rabbits. After 30 min. the animals were killed and thepost mortemaccumulation of PGE2and PGF2αin the renal medulla was determined by mass fragmentography. In control animals, the accumulated levels of PGE2and PGF2αin the medulla were 9.2±2.2 (S.D.) and 1.5 ± 0.6 μg/g, respectively. Dose‐dependent inhibition was demonstrated with all the drugs. The ED95 was for aspirin 15 mg/kg, for diclofenac sodium 1.5 mg/kg, for indomethacin 1.5 mg/kg and for d‐naproxen 5 mg/kg. The duration of inhibition was studied by radioimmunoassay in anaesthetized rabbits by following the urinary excretion of PGF2αand PGE2after an intravenous injection of solvent or test drug in doses twice the ED95. For three hours following aspirin, diclofenac sodium, indomethacin and d‐naproxen, the decreases in urinary excretion of PGF2αranged from 64 to 88, 87 to 95, 64 to 90 and from 40 to 77 per cent of the control, respectively, and the decreases in PGE2excretion were of similar magnitude. Together these results indicate that diclofenac sodium might be used as a long‐lasting and potent alternative to indomethacin and aspirin in experimental studies on the renal PG systemin vivo.
Biochemical and Morphological Characterization of Subcellular Fractions Isolated from Rabbit Colon Muscle
Authors: Nilsson Karin B. , Andersson Rolf G. G. , Eneström Sverker , Mackerlova Ludmila , Mohme‐Lundholm Ella
Published: July 2010

AbstractFrom a homogenate of rabbit colon muscle subcellular fractions were isolated by differential centrifugation. The crude microsomal fraction could be separated into subfractions, a fraction of vesicular microsomes at 35% sucrose, a fraction containing sarcolemma, mitochondrial fragments and microsomal vesicles at 35–45% sucrose and a small protein fraction at 45–55% sucrose. Their biochemical properties and their morphological characterization were investigated. The cholesterol and the phospholipid content was equally distributed between the microsomal fractions 35% and 35–45% while the RNA was localized to the mitochondria and the microsomal fraction 35%. The enzyme cytochrome c oxidase was found to be concentrated in the mitochondria while a high contamination was found in the microsomal fractions 35–45%. The NADH‐oxidase activity was highest in the 35% fraction and the 5′‐nucleotidase activity in the 40,000 × g supernatant. The microsomal subfractions contained the enzymes ATPase, adenylate cyclase and phosphodiesterase. In the 35% fraction Ca stimulated the hydrolysis of ATP. The binding of [3H]‐ouabain and the incorporation of [3H]‐leucine was most pronounced in the 35% fraction. In a K+‐free Krebs Ringer medium the binding of the glucoside was stimulated in all the fractions. From these results we concluded that the fraction 35% sucrose may be mainly derived from the endoplasmic reticulum and the plasma membrane while the 35–45% originates from the plasma membrane, mitochondria and to a lesser extent the endoplasmic reticulum.
Effects of Different Cyclophosphamide Treatment Schedules on Collagen and Collagenolytic Activity in Granulation Tissue
Authors: Hansen T. Mørk , Prause J. U. , Lorenzen I.
Published: July 2010

AbstractCyclophosphamide was injected intraperitoneally into rats in doses of 6 or 10 mg/kg/day. The controls had daily intraperitoneal injections of physiological saline. After 14 days of treatment, granulation tissue was produced by subcutaneous implantation of viscose cellulose sponges. The treatment with cyclophosphamide and physiological saline was continued in different sequences for a further one or two 14‐day periods. The rats were killed 14 or 28 days after the sponge implantation. Cyclophosphamide caused a decrease in body weight, in the number of leucocytes, in granuloma dry weight and in the granuloma content of free OH‐proline while the water percentage increased. Ten mg/kg/day of cyclophosphamide had a more pronounced effect than 6 mg/kg/day. The results are consistent with an inhibitory effect of cyclophosphamide on granuloma formation and on the degradation of collagen. Accordingly, measurements of collagenolytic activity in granulation tissue after culturein vitrosuggested an inhibition of collagenolysis after cyclophosphamide treatment. No effect of pretreatment was observed, and the effect of cyclophosphamide was independent of whether cyclophosphamide was given during the early or late phase of granulation tissue production.
Pharmacokinetics of Theophylline in Ten Elderly Patients
Authors: Nielsen‐Kudsk F. , Magnussen I. , Jakobsen P.
Published: July 2010

AbstractThe two‐compartment pharmacokinetics of theophylline in ten hospitalized elderly patients with apparently normal renal, hepatic and cardiopulmonary functions was investigated after intravenous administration of the drug. Nine patients suffered from slight hemiparesis and one from Parkinson's disease. Biological theophylline half‐lives of 5.4–9.0 hours and plasma clearence values of 28–42 ml kg‐1hr‐1were found. The apparent volumes of distribution during the β‐phase, Vdβ, were 0.33–0.43 1 kg‐1. It is concluded that a therapeutic concentration of about 10 μg theophylline per ml serum could be established in the investigated group of elderly patients following an intravenous initial loading dose of 3.7 mg theophylline per kg followed by a continuous infusion of 0.35 mg per kg body weight per hour. In the therapeutic use of theophylline monitoring of the serum theophylline concentration is generally advised because of the elsewhere reported variability in the biological half‐life of the compound.
Effects of Pure Chlorobiphenyls (2,4′,5‐Trichlorobiphenyl and 2,2′,4,4′,5,5′‐Hexachlorobiphenyl) on the Post‐Natal Growth in Mice
Authors: Örberg Jan
Published: July 2010

AbstractThe post‐natal growth rate of young mice, pre‐ and post‐natally exposed to either 2,4′,5‐trichlorobiphenyl or 2,2′,4,4′,5,5′‐hexachlorobiphenyl has been studied. The results show that both the chlorobiphenyls have the ability to increase the post‐natal growth rate in mice and they indicate that this ability of 2,4′,5‐trichlorobiphenyl is most pronounced in females whereas that of 2,2′,4,4′,5,5′‐hexachlorobiphenyl is most pronounced in males.
Simultaneous and Specific Determination of Proxyphylline, Theophylline and other Xanthine Derivatives in Serum by High Pressure Liquid Chromatography
Authors: Nielsen‐Kudsk F. , Pedersen A. Kirstein
Published: July 2010

AbstractA HPLC‐method for rapid, simultaneous and specific determination of proxyphylline, theophylline, glyphylline, theobromine, caffeine and 3‐methylxanthine using 8‐chlorotheophylline as internal standard is presented. Using 20 μl deproteinised serum samples for injection, the detection limits for theophylline and proxyphylline are about 0.040 and 0.055 μg per ml serum or plasma, respectively, and the corresponding sensitivities are about 0.033 and 0.048 μg compound for 0.0044 absorbance units at 280 nm. In duplicate analyses the coefficient of variation is less than 3%. A number of frequently used drugs did not interfere in the analyses of serum samples from patients under treatment or in experiments with drug additions to serum samples.
Myocardial Pharmacokinetics of Lithiumin Vitro
Authors: Nielsen‐Kudsk F. , Pedersen A. Kirstein
Published: July 2010

AbstractThe myocardial pharmacokinetics of ionised lithium were investigated in isolated, intact rabbit hearts, which were retrogradely perfused with a modified Krebs‐Henseleit solution containing lithium in a concentration of 5 mM. The rate of myocardial accumulation of lithium as a function of time was indirectly followed at constant coronary flow by means of determinations of the lithium content of fractional samples of the coronary output of perfusate collected during the lithium perfusion period. The disposition rate of lithium from the myocardium was similarly determined with respect to the time lapse after the perfusion had been switched over to a lithium‐free liquid. The accumulation and disposition processes were found to fit bi‐exponential functions, as an expression of the myocardium behaving as a two‐compartment system obeying apparently first order, linear kinetics with respect to ionised lithium. A pronounced decrease of the uncomposite elimination rate constants k10and especially k21was observed after continuous perfusion with 5 mM lithium perfusion liquid for about 30 min. During this perfusion period at steady state, an absolute increase of myocardial lithium accumulation obviously took place. A possible correlation of these findings to the cardiac effects of lithium is discussed.
A Comparative Study of Serum Creatine Phosphokinase (CPK) Activity in Rabbits, Pigs and Humans after Intramuscular Injection of Local Damaging Drugs*
Authors: Steiness Eva , Rasmussen Folke , Svendsen Ove , Nielsen Poui
Published: July 2010

Abstract Serum creatine phosphokinase (CPK) activity has been determined before and after intramuscular injection of lidocaine, diazepam or saline in humans and lidocaine, diazepam, digoxin and saline in pigs and rabbits. Two ml volume of each of the drugs was given to humans as well as to the experimental animals. No changes in CPK activity were found after saline in humans or rabbits but a minor increase was demonstrated in pigs. A marked increase of CPK activity was demonstrated after lidocaine or diazepam in humans and after lidocaine, diazepam or digoxin in pigs and rabbits. Post mortem examination of the injection sites in the animals revealed extensive muscle tissue necrosis after lidocaine, diazepam and digoxin. No damage of the tissue was found after saline. CPK activity was also determined in rabbits receiving 2 ml of dilutions of diazepam in saline. The injection sites were examined post mortem. The CPK activity was increased in animals receiving 1:2 and 1:8 dilutions while a 1:20 dilution did not give rise to changes in the enzyme activity. The necrotic area diminished when diazepam was diluted and no pathological changes were found at the injection sites after the 1:20 dilution. Measuring the CPK activity in rabbits after an intramuscular injection seems to be a sensitive method for the determination of local toxicity.
Effects of Isoprenaline and Dibutyryl‐C‐AMP on the Electrical and Mechanical Activity of the Rabbit Myometrium
Authors: Nesheim Britt‐Ingjerd , Sigurdsson Stefan B.
Published: July 2010

AbstractMechanical and electrical responses of spontaneously contracting muscle strips from oestrogen dominated rabbit uterus were investigated by the sucrose gap method. The effects of isoprenaline and dibutyryl‐c‐AMP in the presence and absence of propranolol were tested. It has been shown previously that the β‐adrenoceptor agonist isoprenaline inhibits the spontaneously contracting uterus even in the presence of the β‐blocker propranolol. The rise in c‐AMP which is caused by isoprenaline, is, however, blocked by propranolol. The aim of this investigation was to study further the role of c‐AMP in the isoprenaline‐induced relaxation of the uterus.

Isoprenaline (10‐6M) consistently abolished spikes and mechanical contractions, usually accompanied by hyperpolarization. Propranolol (3 × 10‐6M) markedly reduced the incidence of hyperpolarization, but did not affect the other actions of isoprenaline. Hyperpolarization does not seem to be a prerequisite for inhibition of uterine contraction. Dibutyryl‐c‐AMP mimicked the actions of isoprenaline. No positive evidence to support a hypothesis of a c‐AMP‐independent mechanism was found. Therefore a possible explanation of the results could be that isoprenaline increases c‐AMP in a small intracellular pool, mediating electrical and mechanical responses but not influenced by propranolol.
Influence of Citalopram and Chlorimipramine on Uptake of 5‐HT by Isolated Perfused Guinea Pig Lungs
Authors: Fjalland B.
Published: July 2010

AbstractA method is described for the preparation and perfusionin vitroof isolated guinea pig lungs. 5‐HT is rapidly taken up from a perfusing solution by this organ (about 70% uptake). In the concentration range 10‐7to 5 × 10‐6M citalopram concentration dependently inhibited the uptake of 5‐HT by the lung preparation. Chlorimipramine inhibited the uptake of 5‐HT only by 40–50%, and the inhibition was not concentration dependent. The method used seems to be a reliable model for studying the uptake of 5‐HT.
Effects of Cortisol Administration on Components of the Hepatic Microsomal Mixed Function Oxidase System (MFO) of Immature Rainbow Trout (Salmo gairdnerii Rich.)
Authors: Hansson Tiiu , Lidman Ulf
Published: July 2010

AbstractThe effects of cortisol on components of the liver microsomal mixed function oxidase system (MFO) of immature and starved rainbow trout,Salmo gairdnerii, Rich., were studied 3, 7 and 21 days after intraperitoneal implantation of cortisol‐containing cholesterol pellets. The treatment resulted in significantly elevated NADPH cytochrome c reductase activities, concomitant with elevated plasma cortisol levels, at all sampling events, while no significant effects on either liver cytochrome P‐450 or microsomal protein contents was observed. The cortisol‐treated fish lost considerably more body weight than corresponding controls during the experimental period, while the effects on liver wet weight and liver somatic index were inconclusive.
Changes in the Sensitivity of Dopamine Receptors in the Nucleus Accumbens and in the Striatum Induced by Chronic Ethanol Administration
Authors: Liljequist Sture
Published: July 2010

AbstractRats of the Sprague‐Dawley strain were maintained on ad libitum food and a forced‐intake regimen of ethanol for up to 270 days. Bilateral application of dopamine (DA) into the nucleus accumbens of both chronic ethanol rats and rats undergoing withdrawal produced a pronounced increase in coordinated locomotor activity which was 8–10 times higher than that of untreated water control rats. This phenomenon was first observed after 5 months of ethanol treatment and lasted for about 4 weeks after cessation of the treatment. It is concluded that prolonged ethanol administration produces an increased sensitivity of the DA‐receptors in the nucleus accumbens and further supports the contention that central catecholamine mechanisms are involved in the mediation of the withdrawal syndrome observed after chronic treatment with ethanol.
The Influence of Protein Binding on the Pharmacokinetics of Sulphadimethoxine in Rabbits
Authors: Ladefoged Ole
Published: July 2010

AbstractThe pharmacokinetics of sulphadimethoxine was investigated in rabbits at five dose levels. A significant nonlinearity of dose dependent pharmacokinetics was demonstrated. A large dose dependent change in per cent of sulphadimethoxine bound to plasma proteins was shown. It is concluded that the nonlinearity of the pharmacokinetics of sulphadimethoxine is mainly caused by the dose dependent changes in per cent of drug bound to plasma proteins.
Lithium Chloride Toxicity and Pharmacodynamics in Inbred Mice
Authors: Smith Donald F.
Published: July 2010

AbstractInbred strains of male mice (C3H, DBA, BALB, C57) were used to determine whether genetic factors play a role in lithium toxicity. Significant differences in the LD50 for LiCl were observed between the mouse strains after a subcutaneous injection of 37° isotonic LiCl. The LD50 values in the C3H, DBA, BALB and C57 strains were 17.4, 17.6, 18.2 and 19.4 mmol/kg, respectively. Significant differences were also observed between the mouse strains in the concentrations of lithium in plasma, heart, liver, kidney and brain 2 hrs. after a subcutaneous injection of 15.1 or 18.2 mmol/kg LiCl, but the lithium concentrations were not related in an obvious manner to LiCl toxicity. The results show that genetic factors can influence the toxicity and pharmacodynamics of lithium.
The Significance of Lymphocyte Lipid Changes after Smoking Hashish
Authors: Kalofoutis A. , Koutselinis A. , Dionyssiou‐Asteriou A. , Miras C.
Published: July 2010

Abstract The increase of lymphocyte total lipids and phospholipids after smoking hashish, indicates either a lipid transfer from their site of production after smoking the drug or a mobilization of their biosynthetic mechanism in the lymphocyte. A fluctuation of individual phospholipid concentrations after “smoking” is related to the influence of certain hashish compounds on the various biosynthetic pathways of phospholipids in lymphocytes. Changes in phosphatidylcholine, phosphatidylinositol and phosphatidylserine are related to a possible fluctuation of the overall immune ability of the lymphocyte, by affecting the lymphocyte membrane enzyme mechanisms.
Effect of Melperone, Two of its Metabolites and Thiothixene on Central Monoamine Metabolism and Prolactin Levels in Rodents
Authors: Wiesel Frits‐Axel , Bjerkenstedt Lars , Skett Paul
Published: July 2010

Abstract The effects of melperone and thiothixene on the concentrations of monoamine metabolites in brain and prolactin in the serum of rats and mice were determined. Both drugs increased brain concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in a dosedependent manner. 5‐Hydroxyindoleacetic acid (5‐HIAA) was unaffected. The effect of thiothixene was longer lasting and about 5 times greater than that of melperone. Melperone, but not thiothixene, increased levels of 3‐methoxy‐4‐hydroxyphenylethylene glycol (MOPEG). Several hours after administration of melperone, levels of HVA and MOPEG were diminished.

Both drugs increased prolactin concentrations in rat serum. Thiothixene was about 10 times more potent than melperone.

Of two urinary metabolites of melperone investigated, one caused the same qualitative effects on monoamine metabolism as melperone itself but with reduced potency. The other metabolite was ineffective.
Transport and Binding of Lidocaine By Lung Slices and Perfused Lung of Rats
Authors: Post C. , Andersson R.G.G. , Ryrfeldt Å. , Nilsson E.
Published: July 2010

AbstractThe accumulation of radioisotopically labelled lidocaine was investigated in lung slices and perfused lungs of rats. Lidocaine was taken up by rat lung slices incubated in an oxygenated physiological solution (pH 7.4) at 37°.14C‐lidocaine accumulated in lung slices to a much greater extent than did3H‐sucrose, and the lidocaine space was approximately 7 times that of the extracellular space. No metabolism of lidocaine took place during the incubation period. The accumulation of lidocaine was inhibited by low temperature, while anaerobic conditions had no inhibitor effect. The uptake of lidocaine (0.028 mM) was slightly antagonized by high concentrations of Ca2+(10 mM).

The isolated perfused lung model was used for studying the pulmonary absorption of lidocaine from the vascular bed. Lidocaine was rapidly extracted from the perfusion solution and the drug appeared to accumulate in at least two compartments. It seems that in the rat lung a portion of the lidocaine taken up had accumulated within the cells, while som of it may be fixed to the cell surfaces.
Pharmacokinetics of Clomethiazole in Healthy Adults
Authors: Jostell K.‐G. , Agurell S. , Allgén L.‐G. , Kuylenstierna B. , Lindgren J.‐E. , Åberg G. , Österlöf G.
Published: July 2010

Abstract The systemic availability of clomethiazole was assessed by comparing blood levels after intravenous and oral administration. Clomethiazole was rapidly absorbed after oral administration to volunteers, particularly when administered as syrup. The fraction of the given dose that reached the systemic circulation after 1 capsule of clomethiazole (192 mg clomethiazole) was 0.25±0.18, after 2 capsules (384 mg clomethiazole) 0.38±0.18, and after 15 ml syrup (480 mg clomethiazole) 0.42±0.20. The time‐blood concentration profiles were consistent with a two‐compartment open model and the mean elimination half‐lives of 3.6‐5.0 hrs. were found for the different formulations and administration routes. Elimination half‐lives showed little variation and a mean systemic clearance of 49 ml/min./kg was found for clomethiazole after intravenous administration. Clomethiazole is bound to human plasma proteins (63.4±1.6%, 37°), a binding which is not affected by Vacutainer® sample tubes. The blood/plasma distribution of clomethiazole was 0.76±0.02 at 37°. A sensitive mass fragmentographic assay for the determination of clomethiazole in blood/plasma down to levels of 1 ng/ml (6.2 nmol/l) is described.
The Degree of Methylation and Organ Distribution of Mercury in Some Birds of Prey in Norway
Authors: Norheim Gunnar , Frøslle Arne
Published: July 2010

Abstract The concentrations of total mercury and methyl mercury were determined in organs from several species of birds of prey. The organ distributions were calculated for each species. For total and non‐methyl mercury, significant differences were found between the species. For methyl mercury no such differences were found. The liver: kidney ratios in White‐tailed Eagle were 1:2.4 and 1:0.9 for total and methyl mercury, respectively. The corresponding figures for the Eagle Owl were 1:0.7 and 1:0.8. The distribution pattern and the degree of methylation were mainly dependent on the mercury levels, and there seemed to be an inverse relationship between the total mercury levels and the percentages of methyl mercury in the organs, especially in the kidney. There were good correlations between the methyl mercury concentrations in the liver, kidney, and muscle. The demethylation of methyl mercury seems to be a significant detoxication route for methyl mercury in birds of prey.
The Influence of Ethanol Pretreatment on the Effects of Nine Hepatotoxic Agents
Authors: Strubelt O. , Obermeier F. , Siegers C.P.
Published: July 2010

AbstractThe hepatotoxic effects of carbon tetrachloride (0.01 ml/kg i.p.), thioacetamide (50 mg/kg intraperitoneally), paracetamol (0.5 g/kg intraperitoneally), and allyl alcohol (0.05 ml/kg intraperitoneally) as estimated by determination of serum enzyme activities (GOT, GPT, SDH) were enhanced in mice treated with one oral dose of 4.8 g/kg ethanol 16 hrs. previously. Pretreatment of mice with ethanol did not increase the hepatotoxic actions of bromobenzene (0.25 ml/kg intraperitoneally), phalloidin (1.5 mg/kg intraperitoneally), α‐amanitin (0.75 mg/kg intraperitoneally), and praseodymium (12 mg/kg intravenously) though there was a trend to higher enzyme activities in the case of bromobenzene. In guinea‐pigs ethanol also aggravated CCl4‐induced liver damage, but only strengthened the hepatotoxic activity of D‐galactosamine (150 mg/kg intraperitoneally). Treatment with 4.8 g/kg ethanol did not influence liver glutathione levels in mice but increased aniline hydroxylation in the 9000 × g liver homogenate supernatant of mice and guinea‐pigs. A dose of 2.4 g/kg ethanol, on the other hand, neither increased aniline hydroxylase activity nor enhanced carbon tetrachloride‐induced hepatotoxicity in mice. It is assumed that the enhanced sensitivity to hepatotoxic agents after treatment with ethanol may be due to an enhanced microsomal activation of these substances.
Effect of Fluoride on the Activity of Ornithine Decarboxylase in Normal and Fluoride Resistant LS Cells
Authors: Hongslo Jan K. , Alfheim Ingrid
Published: July 2010

Abstract Renewal of growth medium caused an induction of ornithine decarboxylase (ODC) activity in LS cells grown in suspension culture. Addition of low concentrations of fluoride ions to the growth medium (up to 1.3 mM) resulted in a further increase in this induction of ODC‐activity, whereas addition of 6 mM fluoride caused an inhibition of the induction and resulted in reduced ODC‐activity as compared to controls.

Since sodium fluoride had no stimulatory or inhibitory effect on the ODC‐activity assay, it is likely that the effect is exerted on the regulation of ODC‐activity in the cells. The effect of fluoride ions on the induction of ODC‐activity upon renewal of the growth medium was markedly less pronounced in fluoride resistant LS cells.
Inhibition of Prostaglandin Synthesis in Rat Brain
Authors: Abdel‐Halim M. S. , Sjöquist B. , Änggård E.
Published: July 2010

AbstractRats were injected with one of five drugs alleged to inhibit brain prostaglandin (PG) synthesis: indomethacin, diclofenac, naproxen, aspirin and paracetamol. Animals were killed after 30 min. and the endogenous formation of PGF2αand PGE2in brain homogenates was measured by mass fragmentography using deuterium labelled PGF2αand PGE2as internal standards. Diclofenac, indomethacin, and naproxen inhibited dose dependently, the synthesis of PGF2α. The ED50 for diclofenac was 0.4 mg/kg, for indomethacin 1 mg/kg and for naproxen 2 mg/kg. In equieffective doses indomethacin had the longest duration. The time taken for the inhibition to decline to half its maximal value was 32 hrs for indomethacin and about 15 hrs for diclofenac and naproxen. Under the present conditions aspirin and paracetamol failed to produce significant reduction of PG synthesis in the rat brain homogenates in doses up to 100 mg/kg.
Beta‐adrenoceptor Stimulation and Cyclic AMP Levels in Bovine Tracheal Muscle of Old and Young Animals
Authors: Andersson Rolf G. G. , Kövesi Gyula , Ericsson Eva
Published: July 2010

AbstractThe relationship between cyclic AMP levels and mechanical activity after exposure to isoprenaline was studied in tracheal smooth muscle. It was found that the basal cyclic AMP content decreased with age. The relaxing effects of isoprenaline, theophylline and papaverine were tested on muscles contracted by histamine, acetylcholine or carbacholine. Isoprenaline completely relaxed histamine contracted tracheas, but not those contracted by acetylcholine or carbacholine. Theophylline and papaverine completely relaxed the tracheas irrespective of whether the contracting agent was histamine, acetylcholine or carbacholine. Isoprenaline increased the cyclic AMP content of bovine trachea; this effect was stronger in muscles with spontaneous tension than in histamine contracted muscles. In muscles contracted by carbachol, isoprenaline increased the cyclic AMP level after 5 min. The correlations between the changes in the cyclic AMP levels and the tension in tracheal smooth muscle support the hypothesis that this nucleotide plays a role in the relaxation process.
Reflex Mechanisms for Bladder Inhibition
Authors: Fall Magnus
Published: July 2010

Abstract Continence of urine requires ability of the bladder to maintain a low intravesical pressure at increasing filling, in order to preserve a positive urethral‐bladder pressure gradient. During micturition the conditions are reversed: the bladder has to generate pressures exceeding the urethral pressure, which also presupposes that the urethra opens and remains open as long as is required for all urine to be expelled. These events are made possible by a complicated pattern of central and peripheral neural responses, affecting the bladder‐urethral unit. The pioneer work of determining the reflex mechanisms involved in the regulation of the lower urinary tract was done at the beginning of this century. Recently, further studies have been made and by means of electrophysiological investigations previous data have been confirmed. In this communication some important observations are reviewed and one example is given of how bladder inhibitory reflexes are utilized in therapy.
Frequency‐Dependence of the Metabolism of3H‐Noradrenaline Released from Rabbit Isolated Aorta: Effects of a Combination of Cocaine and Corticosterone or Hydrocortisone
Authors: Schrold Jergen , Nedergaard Ove A.
Published: July 2010

AbstractThe effect of cocaine (neuronal uptake inhibitor) in combination with either hydrocortisone or corticosterone (extraneuronal uptake inhibitors) on the metabolism of3H‐noradrenaline (3H‐NA) released spontaneously or by electrical‐field stimulation was studied on the isolated rabbit aorta preloaded with3H‐NA. In the spontaneous outflow3H‐O‐methylated and deaminated metabolites (3H‐OMDA) accounted for 41% of the total radioactivity whereas3H‐NA represented only 22%. Cocaine (3 × 10‐5M) + hydrocortisone (10‐4M) neither changed the spontaneous outflow of total tritium nor the distribution of the3H‐outflow on3H‐NA and its3H‐metabolites. However, cocaine (3 × 100‐5M) + corticosterone (4 × 10‐5M) enhanced the passive3H‐outflow, increased the percentage recovered as3H‐3,4‐dihydroxyphenylglycol (3H‐DOPEG), and reduced the percentage of3H‐OMDA +3H‐NMN. The effect of field‐stimulation was investigatedduringandofterstimulation at two frequencies: 3 and 10 Hz. The stimulation‐induced3H‐overflow consisted mainly of unmetabolized3H‐NA and3H‐OMDA in the sample collectedduringstimulation. The ratio between3H‐NA and3H‐OMDA was strongly dependent on the frequency of stimulation, Thus it was 1:2 at 3 Hz, but 3:1 at 10 Hz. These ratios were about the same during the poststimulation period. On the other hand, whereas the formation of3H‐DOPEG from3H‐NA releasedduringstimulation at both frequencies was small, it increased rapidly in the poststimulation sample. At 3 Hz, inhibition of neuronal and extraneuronal uptake by cocaine + steroids did not change the stimulation‐induced3H‐overflow, but the distribution on3H‐NA and3H‐metabolites was markedly altered. Thus the percentage of3H‐N A was doubled,3H‐OMDA was halved, and3H‐DOPEG was almost abolished. At 10 Hz, however, cocaine + corticosterone decreased the stimulation‐induced3H‐overflow, but did not change the proportions of3H‐NA and3H‐OMDA. Only the formation of3H‐DOPEG was markedly reduced. It is concluded that the distribution of stimulation‐induced3H‐overflow on3H‐NA and its3H‐metabolites and the effect of neuronal and extraneuronal uptake inhibition on this is strongly influenced by the frequency of stimulation. Furthermore, inhibition of both neuronal and extraneuronal uptake does not fully prevent metabolism of3H‐NA released by electrical‐field stimulation.
Lithium Inhibition of the Antidiuretic Response to a New Specific Cyclic AMP Analogue (ClPheS‐CAMP) in Rats
Authors: Christensen Sten
Published: July 2010

AbstractThe antidiuretic responses to 0.5 mU of arginine vasopressin (AVP) and 3 μmol of 8‐(p‐chlorophenylthio)‐adenosine‐3′,5′‐cyclic monophosphate (ClPheS‐CAMP) were studied in inactin‐anaesthetized rats kept in water diuresis by hypotonic glucose‐saline infusion. Both agents produced short‐term antidiuresis as manifested by a decrease of urine flow and an increase of urine osmolality. Neither agent affected the rate of urinary excretion of creatinine. ClPheS‐CAMP in addition increased total solute excretion, suggesting that the antidiuresis produced by this compound was associated with natriuresis. The more specific antidiuretic response induced by ClPheS‐CAMP, as compared with previous analogues, may be due to its higher affinity to cyclic AMP dependent protein kinase in the collecting duct cells. Rats with polyuria induced by long‐term lithium administration showed no antidiuretic response to AVP, nor to ClPheS‐CAMP. The latter observation provides evidence that the concentrating defect caused by lithium is associated with impairment of the ADH‐response at some step following cyclic AMP formation.
The Effect of Nifedipine on the Monophasic Action Potential and Refractoriness of the Right Ventricle of the Dog Heartin Situafter β‐Adrenergic Receptor Blockade
Authors: Amlie Jan P. , Refsum Helge , Landmark Knud
Published: July 2010

AbstractThe effect of nifedipine, a calcium‐antagonistic drug, was studied on the electrophysiology of the right ventricle in the dog heartin situ. Monophasic action potential recordings were obtained by the suction electrode technique and refractoriness was measured by means of programmed electrical stimulation. Pentobarbitdl anaesthesia was used. As the basic cardiac effects of nifedipine can be altered by the release of catecholamines from sympathetic nerves of the heart and vessels, the dogs were pretreated with the β‐adrenergic receptor blocking agent acebutolol which increased the action potential duration and the refractoriness. Intravenous injection of nifedipine 30 μg/kg body weight decreased the times for 50 and 90 per cent repolarization of the monophasic action potential and to a smaller extent the effective and functional refractory period. It is suggested that nifedipine decreases the action potential duration and the refractoriness of the right ventricle of the dog heartin situdue to a direct effect of the drug on the myocardium.