bluuebunny/crossref_metadata_2025 huggingface dataset:
The Influence of Biperiden in Overdose on Respiration and Circulation in the Dog
Authors: Sangster B. , Zimmerman A. N. E. , van Heijst A. N. P.
Published: July 2010

Abstract Biperiden lactate was administered intravenously in overdose to dogs under general anaesthesia. Biperiden appeared to have a toxic influence on respiration and circulation independently. Respiratory arrest occurred at a dose of 33 ± 10 mg/kg and has probably a central origin. When artificial ventilation was instituted circulatory standstill occurred at a dose of 45 ± 5 mg/kg. The toxic influence of biperiden is characterised by a decrease of heart rate and of left ventricular contractility resulting in cardiogenic shock, Biperiden is compared with orphenadrine as far as its potential hazard is concerned for patients trying to commit suicide by ingesting an overdose.
Organic Anion and Cation Transportin Vitroby Dog Choroid Plexus: Effects of Neuroleptics and Tricyclic Antidepressants
Authors: Bárány Ernst H.
Published: July 2010

AbstractDog lateral choroid plexus accumulates the cation14C‐emepronium and the divalent anion125I‐iodipamidein vitro. At 10 μM, high potency neuroleptics with a substituted piperazine side chain and also haloperidol depress only the uptake of the cation and even stimulate the uptake of the anion. In contrast, at 1‐10 μM, the accumulation ofbothtest substances is inhibited by neuroleptics and tricyclic antidepressants with an aliphatic side chain. Such unspecific effects on seemingly unrelated transport systems at concentrations reached clinically in the CSF might explain some side actions of low potency neuroleptics and antidepressants.
Effect of Di‐(2‐ethylhexyl) Phthalate on Rat Liver Injured by Chronic Carbon Tetrachloride Treatment
Authors: Seth Prahlad K. , Srivastava S. P. , Mushtaq Mohammad , Agarwal D. K. , Chandra Satya V.
Published: July 2010

AbstractThe effect of Di‐(2‐ethylhexyl) phthalate (DEHP), a widely used plasticizer, was studied using histopathological and biochemical parameters on rat liver injured by carbon tetrachloride (CCl4). The mild centrilobular necrosis observed with CCl4(7.7 mmol/kg subcutaneously and biweekly up to 38 days) and mild congestion and bile duct proliferation produced by DEHP (2.5 mmol/kg intraperitoneally daily for ten days after the day 28 of experiment) were modified into extensive necrosis of the parenchymal cells when the animals received both chemicals. Groups of hepatocytes mostly at the periphery of the lobules also showed coagulative necrosis and some central and portal veins were completely occluded. Alterations in the activity of serum and liver enzymes of the animals receiving both chemicals were not significantly different from those treated with CCL alone, except in case of glucose‐6‐phosphatase (G‐6‐Pase) and SGPT. The characteristic decrease of G‐6‐Pase and increase of SGPT was less marked. Although the exact mechanism of the chemical interaction between CCl4and DEHP is not known, the results indicate their combined toxic potentiality.
Interactions of Surface‐active Alkyltrimethylammonium Salts with the Plasma Membrane ofAcanthamoeba castellanii
Authors: Isomaa Boris , Paatero Gun , Lönnqvist Christer
Published: July 2010

AbstractThe interactions of three surface‐active alkyltrimethylammonium salts (C12‐C16) with the plasma membrane ofAcanthamoeba custellaniiwere studied. The surfactants caused a release of K+from the cells at premicellar concentrations. The lytic effectiveness of the surfactants increased with an increase in the length of the alkyl chain with about an order of magnitude for every two carbon atoms added to the alkyl chain. Binding studies with the C16homologue revealed that at a concentration corresponding to 50% release of K+there were about 1.9 × 1010molecules bound per cell. At prelytic concentrations the surfactants stimulated phagocytosis and pinocytosis. The mode of action of the surfactants on the plasma membrane ofAcanthamoeba castellaniiis discussed and it is hypothesized that the stimulation of endocytosis is due to a “fluidizing” effect of the surfactants on the lipid bilayer of the plasma membrane.
Effects of Cholinoceptor Blocking Drugs, Adrenoceptor Stimulants, and Calcium Antagonists on the Transmurally Stimulated Guinea‐pig Urinary Bladderin Vitroandin Vivo
Authors: Sjögren C. , Anderson K.‐E.
Published: July 2010

AbstractThe effects of different drugs on the response to transmural electrical stimulation of the guinea‐pig urinary bladder were studiedin vitroandin vivo. In vitro, atropine (3.0 × 10‐8‐5.9 × 10‐4M) did not influence the contractions. When used in high concentrations (>5.2 × 10‐5M), PR 197, another anticholinergic compound, reduced the responses by 25‐40%, probably by a non‐specific action. Noradrenaline (2.0×10‐6‐2.0 × 10‐4M) and isoprenaline (2.0 × 10‐8‐2.0 × 10‐4M) had concentration‐related inhibitory effects that could be blocked by propranolol (5.2 × 10‐6M). Adenosine (2.0 × 10‐2M) inhibited the response by 27±3% (mean±S.E.M., n = 9). Theophylline (2.0 × 10‐3‐6.0 × 10‐4M) had no consistent effects. The calcium antagonist nifedipine (1.2 × 10‐6‐1.7 × 10‐5M) reduced the contractions by 25‐50%; verapamil (2.2 × 10‐5‐4.4 × 10‐4M) was little effective.In vivo, atropine (10 mg/kg) reduced the contractions by 55±5%(n= 10), whereas PR 197 (5 mg/kg) almost completely suppressed the responses. Noradrenaline (20‐100 μg/kg) and isoprenaline (20‐300 μg/kg) also caused a marked inhibition that could be blocked by propranolol (0.25‐2.0 mg/kg). Theophylline (5 and 10 mg/kg) had a weak (10‐20%) inhibitory effect. Adenosine (3.0 mg/kg) reduced the contractions by 47±4% (n= 14); in guinea‐pigs pretreated with atropine (10 mg/kg), adenosine produced a further 10 to 20% decrease of the responses. Verapamil (0.5‐2.0 mg/kg) had no consistent effect, whereas nifedipine (0.1‐0.2 mg/kg) caused an inhibition of 20‐50%. The results suggest that β‐adrenoceptor stimulants, and drugs with a combined anticholinergic and non‐specific action, can effectively suppress the electrically evoked contractions in the guinea‐pig urinary bladder.
Effects of β‐Adrenoceptor Agonists on Airway Smooth Muscle and on Slow‐contracting Skeletal Muscle:In VitroandIn VivoResults Compared
Authors: Olson O. A. T. , Swanberg E. , Svedinger I. , Waldeck B.
Published: July 2010

AbstractTen β‐adrenoceptor agonists were examined with respect to a) relaxation of pilocarpine‐contracted trachea and depression of contractions of the soleus muscle of the guinea‐pigin vitroand b) counteraction of histamine‐induced bronchospasm and depression of contractions of the soleus muscle of the catin vivo.There was a close correlation between the results obtainedin vitroand results obtained on the corresponding tissuesin vivoin spite of the different species used. A close correlation was also observed between effects on airway smooth muscle and on the soleus muscle contractionsin vitroas well asin vivofor all compounds examined.
Pharmacokinetics of Intravenously Administered L‐5‐Hydroxytryptophan in Man
Authors: Magnussen I. , Nielsen‐Kudsk F.
Published: July 2010

AbstractThe pharmacokinetics of 5‐hydroxytryptophan were investigated in relation to intravenous administration of single doses of the amino acid (0.2 mg/kg b.wt.) to five patients pretreated for one week with carbidopa, an L‐aromatic amino acid decarboxylase inhibitor. The plasma concentration/time lapse of 5‐hydroxytryptophan exhibited bi‐exponential disposition characteristics and the data obtained could be closely fitted to an open two compartment pharmacokinetic model with elimination taking place from the central compartment. The apparent composite 1. order rate constants α and β were 1.433 hr‐1± 0.177 S.D. and 0.113 hi‐1± 0.012 hr‐1S.D., respectively. The biological half‐life of 5‐hydroxytryptophan under the experimental conditions was thus about 6 hours. The apparent volume of the central compartment, Vc, was found to be 0.336 1 kg‐1± 0.059 S.D. and the plasma clearance 0.105 1 hr‐1kg‐1± 0.015 S.D. The derived pharmacokinetic constants were used for doses regimen calculations and predetermination of the plasma concentration/time lapse, during continuous intravenous infusion therapy. Measured plasma concentrations of 5‐hydroxytryptophan during infusion deviated by less than 10 per cent from the predicted values. However, the infusions had to be stopped in four of the experiments because the patients became nauseated and vomited after total doses of only 36‐128 mg.
Effects of m‐Xylene on Human Equilibrium Measured with a Quantitative Method
Authors: Savolainen K. , Linnavuo M.
Published: July 2010

Abstract Swaying during normal upright posture in 17 young males and the effects of m‐xylene exposure on the body sway of six of the 17 has been studied by a cluantitntive Romberg test, conducted with an equipment consisting of a strain gauge transducer platform and of an electronic unit. The exposures were conducted in a dynamic exposure chamber. The sway of the 17 subjects was larger when their eyes were closed than when they were open (P<0.001) indicating thee importance of vision in the control of body balance. Exposure to a time‐weighted average (TWA) concentration of 100 p.p.m. (4.1 μmol/I) of xylene with 200 p.p.m. (8.2 μmol/1) peaks had no observable effect on the body balance of the six subjects. Exposure to a TWA concentration of 200 p.p.m. of xylene with 400 p.p.m. (16.4 μmol/l) peaks ‐ the corresponding mean concentration of xylene in venous blood being 29.1 ± 3.2 μmol/1 ‐ clearly impaired the body balance of the six subjects. The impairment was most pronounced with the eyes closed (P=0.016). The results suggest that human equilibrium is rather sensitive to effects of exposure to xylene.
The Influence of Trichloroethylene and Related Drugs on the Vestibular System
Authors: Tham R. , Larsby B. , Ödkvist L. M. , Norlander B. , Hydén D. , Aschan G. , Bertler Å.
Published: July 2010

A previously described experimental model for studying the effect of industrial solvents on the vestibular system of rabbits has been applied to trichloroethylene. Estimation of trichloroethylene and its metabolites in blood and cerebrospinal fluid was performed by gas chromatography. Vestibular function was studied by recording nystagmus, induced by positional changes or accelerated rotation. At blood levels of trichloroethylene above 30 p.p.m. “positional nystagmus” develops. Two metabolites of trichloroethylene, chloral hydrate and trichloro‐ethanol, which are known as central nervous system (CNS) depressants, did not induce this abnormal nystagmus. However, α‐chloralose, a derivative of chloral hydrate, induced positional nystagmus and also a markedly exaggerated nystagmus developed during rotatory acceleration. It is suggested that solvents like trichloroethylene elicit vestibular disturbances by stimulation of central subcortical vestibulo‐oculomotor connections. The stimulation may be caused by a blockage of inhibitory systems.
Effects of 4‐aminopyridine on Statistical Parameters of Transmitter Release at the Neuromuscular Junction
Authors: Lundh Håkan
Published: July 2010

Abstract4‐Aminopyridine (4‐AP) potentiates transmitter release from motor nerve terminals by increasing the quantum content (m) of endplate potentials. Estimates of the binomial parameters of transmitter release shows that 4‐AP enhances m by increasing n and not p.
Effects of Tetraethyl Lead on the Activities of Drug Metabolizing Enzymes in Different Tissues of the Rat
Authors: Ahotupa Markku , Hartiala Kaarlo , Aitio Antero
Published: July 2010

Abstract The present study describes the effects of tetraethyl lead on various drug metabolizing enzymes in different tissues of the rat. Tetraethyl lead was administered intraperitoneally to rats (250 γmol/kg) on two consecutive days. The animals were killed on day 3. Tetraethyl lead‐treatment decreased the concentration of hepatic cytochrome P‐450 (to 45 per cent of the control), the hepatic activity of aryl hydrocarbon hydroxylase (to 41 per cent of the control) and ethoxycoumarin deethylase (to 45 per cent of the control). Epoxide hydratase activity was enhanced in the liver (1.3‐fold), kidney (3.3‐fold), and small intestinal rnucosa (4.7‐fold). The activity of glutathione S‐transferase decreased in the liver (to 69 per cent of the control) but increased in the kidney (1.5‐fold) and small intestinal mucosa (1.7‐fold). The glucuronidation of o‐aminophenol was enhanced (2.2‐fold) in the kidney of tetraethyl lead treated rats. It is concluded that exposure to tetraethyl lead brings about widespread changes in the ability of mammals to detoxify foreign compounds.
Study of Thioridazine Cardiotoxic Effects by Means of His Bundle Activity Recording***
Authors: Descotes J. , Lievre M. , Ollagnier M. , Fawon G. , Evreux J. CI.
Published: July 2010

AbstractThe effect of thioridazine on sinusal automaticity, myocardial excitability and auriculoventricular conduction have been studied in dogs by measuring the spontaneous heart rate, the effective refractory period of the atrial contractile tissue, the time of auriculonodal and infrahisian conduction. Chloralose anaesthetized dogs were administered 10 mg/kg thioridazine hydrochloride via intravenous route. While sinusal automaticity was not altered, conduction times were prolonged in the suprahisian and mainly the infrahisian part and the atrial refractory period increased. These effects are related to quinidine‐like properties and consistent with cardiotoxic effects previously reported in clinical practice.
Sensitization of the Submaxillary Gland of the Rat after Sympathetic Denervation
Authors: Asking Bengt , Ekström Jörgen
Published: July 2010

AbstractThe sensitivity of the submaxillary gland of the rat to chemical stimuli was examined 1, 4 and 6 weeks after sympathetic denervation. The gland was found to have developed a supersensitivity not only to noradrenaline but also, in contrast to previous reports, to adrenaline and metacholine. The supersensitivity remained unaltered throughout the period of observation.
Effects of Variousin Vitro‐ inhibitors of Benzo(a)pyrene Metabolism in Isolated Rat Lung Perfusion
Authors: Vähäkangas Kirsi , Nevasaari Kaisu , Pelkonen Olavi , Kärki Niilo T.
Published: July 2010

AbstractVariousin vitro‐inhibitors were added with3H‐benzo(a)pyrene (BP) into the perfusion fluids in isolated rat lung perfusions to see whether their effects are dependent on the integrity of tissue.3H‐BP and its metabolites were measured by thin‐layer chromatography and radiometry from both samples of perfusion medium and homogenates of lung tissue. The total covalent binding to lung tissue was used as a measure of the formation of reactive metabolites. In methylcholanthrene‐induced rat lung, the metabolism of BP was inhibited by α‐naphthoflavone, an inhibitor of monooxygenase, and less with diethylmaleate, a depletor of glutathione, with salicylamide, an inhibitor of conjugases, and, astonishingly, with D‐saccharo‐1,4‐lactone, an inhibitor of β‐glucuronidase. With trichloropropene oxide, which inhibits epoxide hydratase, the metabolism was either decreased or unchanged. Nicotine had no effect on BP‐metabolism. Nicotine and diethylmaleate increased statistically significantly and α‐naphthoflavone and salicylamide decreased the covalent binding of radioactivity to lung tissue. In most cases, the changes in BP metabolism observed during perfusion can be explained on the basis of effects of modifiers on the enzyme systems.
Effects of Digoxin on Isolated Human Mesenteric Vessels
Authors: Mikkelsen E. , Andersson K.‐E. , Pedersen O. Lederballe
Published: July 2010

AbstractDigoxin had contractant effects on isolated, human mesenteric arteries and veins. Veins were more sensitive to this action of the glycoside than arteries. The contractions were not affected by phentolamine or by washing with a digoxin‐free solution. However, they were abolished by the calcium antagonist nifedipine, and by washing with a calcium‐free medium. In the presence of digoxin, the maximum response to noradrenaline (1.8 × 10‐5M) increased markedly in both arteries and veins, and the concentration‐response curve for the amine was displaced to the left. Immersion of vein preparations in calcium‐free solution for 30 min. abolished the digoxin contracture; an increase in extracellular calcium restored the response. Changes in extracellular potassium concentration caused changes in tension of the mesenteric veins similar to those previously demonstrated in peripheral veins ‐ both in the presence and in the absence of digoxin. It is concluded that digoxin contracts mesenteric vessels by a direct action on the muscle cells, and potentiates the contractant effects of noradrenaline. These effects are dependent on the availability of extracellular calcium. Mesenteric vascular reactions caused by changes in extracellular potassium are influenced by digoxin.
Glutathione Depletion in Isolated Hepatocytes: Its Relation to Lipid Peroxidation and Cell Damage
Authors: Anundi Irene , Högberg Johan , Stead A. Howard
Published: July 2010

AbstractThe effects of glutathione depletion in isolated hepatocytes have been studied. A list of compounds which depleted glutathione and induced lipid peroxidation and cell lysis is given. The effects of halogenated acetamides were studied in more detail and results of studies on the interaction of iodoacetamide with cellular constituents are presented. A single metabolite of iodoacetamide, tentatively identified as the glutathione conjugate, was excreted from the cells while less than one percent of the “parent compound” was retained, tightly bound to macromolecules. This bound component could not be associated with the cellular damage. Methionine, cysteine and α‐tocopherol, as well as paracetamol and ethylmorphine, were found to prevent lipid peroxidation and lysis. It is concluded that GSH deficiencyper secan lead to lipid peroxidation and that this reaction caused the observed hepatocellular lysis.
Relaxant Effects of Nifedipine on Isolated, Human Myometrium
Authors: Forman A. , Anderson K.‐E. , Person C. G. A. , Ulmsten U.
Published: July 2010

AbstractMyometrial tissue was obtained from non‐pregnant women subjected to hysterectomy because of various gynaecological disorders, and from women undergoing caesarean section. Strip preparations were dissected and isometric tension was recorded. Nifedipine (2.9×10‐8‐2.9×10‐6M) inhibited spontaneous contractile activity, mainly by reducing the amplitude of contraction in both non‐pregnant and pregnant myometrium. The drug also inhibited potassium induced contractions in a concentration dependent manner. This effect seemed to be more pronounced in pregnant than in non‐pregnant tissue. In preparations of pregnant human myometrium, normally polarized or potassium depolarized, oxytocin induced a contractile activity that was effectively inhibited by nifedipine. Nifedipine also relaxed contractions induced by vasopressin in isolated non‐pregnant myometrium. It is concluded that the relaxant effect of nifedipine on isolated pregnant and non‐pregnant human myometrium can be explained by inhibition of calcium influx. The results thus support the view, that calcium influx is an important step in the initiation of contractile activity in human uterine smooth muscle.
Fluoride Inhibition of Protein and DNA Synthesis in Cells in Vitro
Authors: Holland Roy I.
Published: July 2010

Abstract Fluoride concentrations at and above 0.9 mM caused a progressive, concentration‐related inhibition in the incorporation of both 14C‐leucine and 3H‐thymidine in LS cells incubated in medium with serum. The incorporation of leucine was more affected than that of thymidine, Lowering the pH enhanced the effect of fluoride on both. Removing serum from the incubation medium changed the effect of fluoride, particularly at low pH (7.0). Incorporation of leucine was then stimulated by low fluoride concentrations (0.5 and 0.9 mM), and the effect on thymidine incorporation was eradicated up to 1.3 mM‐NaF. No differences were found in the pool and the specific activity of 14C‐leucine in the fluoride exposed cells compared to control cells without fluoride (incubated at pH 7.4 in medium without serum). The cellular pool of 3H‐thymidine decreased markedly during the incubation period, somewhat less in the fluoride exposed cells than in the control.
Mutagenic Activation of Tris(2,3‐dibromopropyl)phosphate: The Role of Microsomal Oxidative Metabolism
Authors: Sóderlund Erik J. , Nelson Sidney D. , Dybing Erik
Published: July 2010

AbstractThe flame retardant tris(2,3‐dibromopropyl)phosphate (Tris‐BP) is converted to products which are mutagenic forSalmonella typhimuriumTA 100 in the presence of rat liver microsomes, NADPH and oxygen. Other bromopropyl‐compounds were also mutagenic; 2,3‐dibromopropene and 2,3‐dibromopropionic acid were directly mutagenic, whereas 2,3‐dibromopropanol and tris(2‐bromopropyl)phosphate were weakly mutagenic after addition of liver microsomes and cofactors. Typicalin vivoandin vitroinhibitors of cytochrome P‐450 inhibited Tris‐BP mutagenicity. The effects of inducers of cytochrome P‐450 on Tris‐BP mutagenicity was dependent on the concentration of mutagen and microsomal protein in the assay, indicating complexity in the kinetics involved when dealing with possible multiple pathways that lead to mutagenicity. Addition of glutathione strongly inhibited Tris‐BP mutagenicity. It is suggested that Tris‐BP is oxidized to a reactive electrophile, possibly the 2‐keto derivative, which could react with nucleophilic groups in DNA and thus lead to mutagenic events.
The Succulent Euphorbias of Nigeria. III. Structure and Potency of the Aromatic Ester Diterpenes of Euphorbia Poissonii Pax
Authors: Evans Fred J. , Schmidt Richard J.
Published: July 2010

Abstract The latex of Euphorbia poissonii was found to contain irritant aromatic diterpene esters based upon resiniferonol, 12‐deoxy‐16‐hydroxy‐phorbol and 12‐deoxyphorbol. Four resiniferonol esters, 9,13,14‐ortho‐phenylacetyl‐resiniferonol‐20‐0‐[p‐hydroxy‐phenylacetate]; 9,13,14‐orthophenylacetyl‐resiniferonol‐20‐0‐[m‐methoxy‐m′‐hydroxy‐phenylacetate]; 9,13,14‐orthophenylacetyl‐resiniferonol‐20‐0‐acetate and resiniferonol‐14‐0‐phenylacetate‐20‐0‐[m‐methoxy‐m′‐hydroxy‐phenylacetate], were identified. Two further esters were identified as 12‐deoxy‐164‐[2‐methylbutyroyl]‐phorbol‐13‐0‐phenylacetate‐204‐acetate and 12‐deoxy‐16‐0‐[2‐methylbutyroyl]‐phorbol‐13‐0‐phenylacetate. These compounds represent the first aromatic esters of this parent diterpene to be obtained from natural sources. The third group of compounds were identified as 12‐deoxyphorbol‐l 3‐0‐[p‐hydroxy‐phenylacetate]‐204‐acetate; 12‐deoxyphorbol‐l 3‐0‐[p‐acetoxyphenylacetate‐20‐0‐acetate; 12‐deoxyphorbol‐13‐0‐phenylacetate‐20‐0‐acetate and 12‐deoxyphorbol‐13‐0‐phenylacetate. The irritant potency of the ten pure compounds was obtained using a mouse ear method for assessment of the irritant dose 50%.
Interaction Studies between Three Antidepressant Drugs (Zimelidine, Imipramine and Chlorimipramine) and Noradrenaline in Healthy Volunteers and some Pharmacokinetics of the Drugs Studied
Authors: Borg K.‐O. , Johnsson G. , Jordö L. , Lundborg P. , Rönn O. , Welin‐Fogelberg I.
Published: July 2010

Abstract The bicyclic compound zimelidine has a pronounced inhibitory effect on neuronal 5‐hydroxytryptamine (5‐HT) uptake in animals. Healthy male volunteers were, in randomized order, given 100 mg zimelidine, 25 mg imipramine and 50 mg chlorimipramine. Before and 90 min after drug intake, increasing doses of noradrenaline was infused (0.006 μg × kg‐1 × min‐1, 0.02 μg × kg‐1 × min.‐1 and 0.06 pg × kg‐1 × min‐1, respectively), and the effect on heart rate and blood pressure was monitored. In some additional experiments N A was infused 4 and 6 hours after oral intake of imipramine and chlorimipramine, respectively. Imipramine in contrast to chlorimipramine and zimelidine potentiated the effects of noradrenaline on the diastolic blood pressure when infused 90 min. after drug intake. When infused 6 hours after oral intake of 50 mg chlorimipramine the effects of noradrenaline were potentiated in two out of three subjects. No anticholinergic effects, measured as blockade of salivary secretion, were observed after any of the three drugs at the doses used. The peak plasma concentration of zimelidine was obtained 2 hours after oral administration and the half‐life of elimination was estimated to about 7 hours. The bioavailability of orally given zimelidine at the studied dose was about 20 per cent. The metabolite desmethylzimelidine was present in the plasma in a similar concentration to that of the parent drug up to 8 hours after oral administration and thereafter in significantly higher concentration indicating a slower rate of elimination for the metabolite. The absorption of imipramine and chlorimipramine from the gastrointestinal tract was rather slow with a peak plasma concentration obtained as late as 6 hours after the drugs were given. The rate of elimination was about the same for imipramine and chlorimipramine and compared to zimelidine these two compounds were more slowly eliminated.
The Binding of Phenprocoumon to Human Plasma Proteins
Authors: Husted S. , Andreasen F.
Published: July 2010

AbstractByin vitroexperiments with equilibrium dialysis and 5 μg PPC per ml an average of 99.7±0.2% was bound to serum proteins. The binding in a solution with the albumin concentration which was present in the Serum samples did not differ from this binding or from the binding in plasma where coagulation was prevented with either heparin or citrate. The binding constant in albumin solutions at 37° was 4.5±0.3 1/molX 10‐5and an average of 1.16±0.04 primary binding sites was found. The association constant for the PPC albumin interaction was temperature dependent and the results of thermodynamic calculations suggested a combined ionic and non‐polar type of binding as the change in enthalpy contributed with 40% of change in free energy. A large positive entropy change was found (15.79 Kcal/mol/°K). The addition of phytomenadione to albumin solutions and of menadione to plasma caused a considerable decrease in the protein bound fraction of PPC, indicating the relevance of a study concerning the possible clinical consequences of these interactions.
Displacement of Nortriptyline and Uptake of14C‐Lidocaine in the Lung after Administration of14C‐Lidocaine to Nortriptyline Intoxicated Pigs
Authors: Post Claes , Lewis David H.
Published: July 2010

AbstractSix anaesthetized Swedish land‐race pigs were intoxicated by an intravenous infusion of nortriptyline‐HCl (NT) up to a concentration of 4.58±0.58 (X±S.E.M.) μM in arterial whole blood. A rapid injection of 2 mg/kg b.wt. lidocaine‐HCl in the right atrium was followed by a rise in arterial whole blood concentration of NT up to a maximum of 7.32± 0.28μM NT. Amount displaced NT from the cardio‐pulmonary circulation after the14C‐lidocaine bolus, was calculated to be 0.66 ± 0.03 μmol. Lung uptake of14C‐lidocaine during first‐pass through the lung was not influenced to any statistically significant degree compared to a control group. Thus, first‐pass uptake (FPU) was 30±8 (X̄±S.E.M.)% and 39±5% respectively. The duration of the QRS‐complex of the ECG was increased (P < 0.01) during the infusion of NT from 0.07±0.01 (X±S.E.M.) sec. to 0.14±0.02 sec. when 250 mg NT‐HCl had been administered. The QRS‐duration was decreased (P<0.01) after the injection of the14C‐lidocaine bolus to 0.09±0.01 sec. Mean arterial blood pressure and heartrate decreased slightly during the infusion of NT, but did not change immediately after the14C‐lidocaine bolus.
Interaction of Salicylates and other Non‐steroidal Anti‐inflammatory Agents in Rats as Shown by Gastro‐ulcerogenic and Anti‐inflammatory Activities, and Plasma Concentrations
Authors: Corell Tim , Jensen Karen Meller
Published: July 2010

AbstractThe interaction of salicylates and other non‐steroidal anti‐inflammatory drugs was studied in rats. Concurrent oral administration of sodium salicylate (SS) or salicylic acid (SA) and indomethacin (IND) significantly reduced the gastro‐ulcerogenicity and the plasma concentrations of IND. Acetylsalicylic acid (ASA) failed to do so. IND had no significant influence on plasma concentrations of SA. Simultaneous administration of SS and IND intraperitoneally or subcutaneously showed the same pattern of interaction as for oral administration. Concurrent oral administration of SS and IND exerted similar anti‐inflammatory activity as the single drugs. SS significantly antagonized the ulcerogenicity of ibuprofen and tended to antagonize the ulcerogenic activity of ASA, phenylbutazone, tolfenamic acid and naproxen. The results suggest that in rats SS and SA (but not ASA) interact with IND concerning both gastro‐ulcerogenicity and plasma concentrations of IND (but not of SA) and that the interaction is systemic in nature. We propose that the ulcerogenic interaction might be explained partly by the reduced IND plasma concentrations and partly by a weaker inhibition by SS of the prostaglandin system in the rat stomach.
Interactions between 1,2‐Propanediol (Propylene Glycol) and Hexobarbital
Authors: Österlind A , Åkesson Å. , Wahlström G.
Published: July 2010

AbstractThe interaction between 1,2‐propanediol and hexobarbital was studied with an anaesthesia threshold method, where hexobarbital is infused intravenously. The dose needed to obtain a burst suppression of one second or more is determined and given as per cent of a pre‐experimental value obtained in the same rat. The effect of varying the interval between the intraperitoneal injection of 1,2‐propanediol (2.06 g/kg) and the threshold determination was investigated. In the intervals, 10‐50 min., the hexobarbital threshold doses were significantly decreased by 13‐27% (n=7‐18). Four different doses between 0.25 and 2.06 g/kg of I,2‐propanediol were then tested after a fixed interval of 30 min. As in the time interval study the thresholds after 2.06 g/kg were significantly decreased. No certain depressant effect was seen with 1.03 and 0.52 g/kg. With the lowest tested dose of 1.2‐propanediol (0.25 g/kg) there was instead a significant increase in the threshold dose (13%). This might be an excitatory effect, which could correspond to the well‐known effect, seen with low doses of other depressants for instance ethanol.
Blood Pressure Response to Ethanol in Relation to Acetaldehyde Levels and Dopamine‐β‐hydroxylase Activity in Rats Pretreated with Disulfiram, Cyanamide and Coprine
Authors: Tottmar O. , Hellström E.
Published: July 2010

AbstractThe blood pressure response after ethanol administration was studied in relation to blood acetaldehyde levels, aldehyde‐dehydrogenase (ALDH) ‐ and dopamine‐β‐hydroxylase (DBH) activities in rats pretreated with the ethanol‐sensitizing compounds disulfiram, cyanamide and coprine and the DBH‐inhibitor FLA‐57. Disulfiram, cyanamide and coprine, but not FLA‐57, inhibited the low‐KmALDH in the liver and caused an increased acetaldehyde level in blood. Disulfiram and FLA‐57, but not cyanamide and coprine, decreased the DBH‐activity in the heart and the levels of norepinephrine in the heart and the brain. In disulfiram‐treated rats with a low DBH‐activity, a fall in blood pressure was observed at acetaldehyde levels being slightly higher than those found in control rats. In disulfiram‐treated rats with a DBH‐activity close to control activity and in rats pretreated with cyanamide or coprine, a fall in blood pressure was found at acetaldehyde levels being 4‐5 times higher than the control level. No effects on blood pressure were observed in rats pretreated with FLA‐57. In rats pretreated with coprine + FLA‐57, the fall in blood pressure was similar, or even lower, than in rats pretreated with coprine alone. The results suggest that acetaldehyde is the main determinant of the hypotension elicited by ethanol in rats pretreated with ALDH‐inhibitors, and that the role of DBH in the disulfiram‐ethanol reaction has been over‐estimated in previous studies.
Cerebrovascular Effects of Central Depressants: A Study of Nitrous Oxide, Halothane, Pentobarbital and Ethanol during Normocapnia and Hypercapnia in the Rat
Authors: Hemmingsen Ralf , Barry David I. , Hertz Marianne M.
Published: July 2010

AbstractThe effect of the central depressants nitrous oxide, halothane, pentobarbital and ethanol upon cerebral blood flow (CBF), cerebral oxygen consumption (CMRO2) and cerebral vascular reactivity to carbon dioxide were measured using the rapid and repetitive intraarterial133Xenon injection technique modified for rat studies. The cerebrovascular resistance (CVR) during normocapnia in the pentobarbital group was significantly higher (P<0.01) than in the nitrous oxide group thus indicating a vasoconstrictor effect of pentobarbital that may be clinically important, because the ability of barbiturates to contract vessels in healthy brain regions may partly explain the protective properties of these drugs against cerebral ischemia. The results indicated that pentobarbital and ethanol may act synergistically with carbon dioxide in depressing CMRO2and cerebral vascular reactivity. Finally, it is concluded that nitrous oxide anaesthesia (70% N2O: 30% O2) is suitable as a reference situation in rat studies of the effect of pharmocological agents on CBF, CMRO2and cerebrovascular reactivity.
5‐HT Antagonism on Cerebral and Common Carotid Arteries by the 5‐HT Uptake Inhibitors Femoxetine and Paroxetine
Authors: Petersen Erling N. , Edvinsson Lars , Hardebo Jan Erik
Published: July 2010

AbstractThe 5‐hydroxytryptamine (5‐HT) antagonism of methysergide was compared with that of the phenylpiperidine 5‐HT uptake inhibitors, paroxetine and femoxetine, using two different models; the isolated cat middle cerebral artery and the common carotid artery of pithed rat perfused with the rat's own blood (autoperfusion). The extracorporeal circulation consisted of about 1.5 ml blood, which was temperature regulated to 36‐38° at the inlet to the carotid vessel by an automatic thermistor coupled heating system. In these experiments systemic blood pressure responses and perfusion pressure responses to 5‐HT were recorded simultaneously. The 5‐HT induced contractile response of the middle cerebral artery was reduced in a non‐competitive way by both uptake inhibitors at concentrations above 0.3 μM which is about 100 times the concentration needed for methysergide. In autoperfusion experiments inhibition was observed only at 5 mg/kg of both drugs. However, methysergide 0.001 mg/kg totally abolished all 5‐HT responses. The uptake inhibitors can therefore be described as weak 5‐HT antagonists.
Influence of Lithium on Cyclic AMP Accumulation in Isolated Rat Fat Cells
Authors: Thams P. , Geisler A.
Published: July 2010

AbstractLithium inhibitsin vitroas well asin vivoseveral hormone‐stimulated adenylate cyclases. The aim of this study was to investigate the mechanism by which lithium inhibits adenylate cyclasein vitro. It was found that lithium inhibited both the norepinephrine‐ and the glucagon‐induced cAMP accumulation in rat fat cells at lithium concentrations above 10 mM. The basal cAMP content was unaffected even at 40 mM of lithium. The inhibitory action was time‐dependent and reversible, indicating an intracellular site of action. Lithium inhibited both norepinephrine‐ and glucagon‐stimulated cAMP accumulation in a mainly non‐competitive way, but the inhibitory effect decreased with increasing hormone concentrations. In accordance, lithium and propranolol had a supraadditive effect on norepinephrine‐induced cAMP accumulation. It is suggested that lithium affects both the hormone‐receptor binding as well as the transfer of the hormonal stimulus by an intracellular site of action.
On the Mechanism of Relaxation of Tracheal Muscle by Theophylline and Other Cyclic Nucleotide Phosphodiesterase Inhibitors
Authors: Fredholm Bertil B. , Brodin Kerstin , Strandberg Kjell
Published: July 2010

AbstractThe mechanism of action of theophylline was studied by investigating the relationship between relaxant effect and inhibition of cyclic nucleotide phosphodiesterase (PDE) and by studying interactions with adenosine actions. Guinea pig tracheal smooth muscle cyclic AMP PDE had two apparent Kms′: 0.4 and 70 μM for cyclic AMP. Theophylline and papaverine competetively inhibited the low Kmform. Hydrolysis of 2.0 μM cyclic AMP and cyclic GMP was inhibited by several drugs. Some agents (e.g. ZK 62 711, ICI 63, 197, Ro 20‐1724, dipyridamol) were considerably more potent as inhibitors of cyclic AMP than of cyclic GMP hydrolysis, while other agents (M & B 22.948 and dilazep) selectively inhibited cyclic GMP breakdown, and some (theophylline, papaverine, IBMX and SQ 20,006) showed little selectivity. There was a weak but significant correlation between inhibition of cyclic AMP phosphodiesterase and relaxation of tracheal smooth musclein vitro. There was also a correlation between the ratio of IC25 cyclic AMP/IC25 cyclic GMP and the smooth muscle relaxation, indicating that inhibition of cyclic AMP rather than cyclic GMP hydrolysis determined relaxation. However, there was a marked tachyphylaxis to the relaxant effect of the cyclic AMP selective PDE‐inhibitors, while the nonselective methylxanthines did not show tachyphylaxis. The effect of theophylline was antagonized by low concentrations of adenosine, which by itself caused a weak tracheal contraction. The effect of PDE‐inhibitors can be partly explained by decreased cyclic AMP breakdown but other mechanisms, such as antagonism of endogenous adenosine, may contribute to the observed relaxant action.
Inhibition of Intestinal Smooth Muscle Contraction by Surface‐active Alkyltrimethylammonium Salts
Authors: Isomaa Boris , Ahlroth Torsten
Published: July 2010

AbstractThe effects of surface‐active alkyltrimethylammonium salts (C10‐C20) on the contractile activity of isolated rat jejunum and on the gastrointestinal motility in anaesthetized rats were studied. The surfactants caused a dose‐dependent depression of spontaneous contractions and of acetyl‐β‐methylcholine and BaCl2induced contractions of isolated rat jejunum. The depressant activity of the surface‐active alkyltrimethylammonium salts on smooth muscle contraction increased with an increase in the length of the alkyl chain to maximum activity at C16. It is suggested that the depressant activity of the surface‐active alkyltrimethylammonium salts on smooth muscle contraction is due to a non‐specific interaction of the surfactants with the cellmembrane of the muscle cells. No effect on gastric and intestinal motilityin vivowas observed following intragastric or intraintestinal administrations of surface‐active alkyltrimethylammonium salts. This lack of effect upon intraintestinal or intragastric administration probably depends on an inability of the surfactants to reach the site of action when administered from the mucosal side.
Enzyme Inducing Effects of Phenobarbital on Nitrazepam Metabolism in Dogs
Authors: Eliander H. , Pekkarinen A.
Published: July 2010

Abstract:A 6‐day peroral phenobarbital treatment of beagle dogs decreased clearly and significantly the mean AUC (1252±270 ng/ml/hr) of a single peroral dose of nitrazepam (1.5 mg/kg), as a sign of enzyme induction to one third (428 ±37 ng/ml/hr P<0.05) in plasma and the concentration maximum (Cmax) (301± 62 ng/ml/hr) to one third (110±15 ng/ml/hr, P<0.05), respectively. The mean Kel, 0.36±0.04, increased to 0.54±0.04 (P<0.05), respectively. An 11‐day phenobarbital treatment decreased the mean AUC of nitrazepam further to one sixth (197±41 ng/ml/hr, P<0.01) and the Cmaxto one fifth (65±10 ng/ml/hr, P<0.01), while the mean Kelincreased from 0.36±0.04 to 0.65±0.02 (P<0.001). The 12‐day peroral nitrazepam treatment showed no sign of autoinduction as a single daily dose. The mean AUC of a single nitrazepam dose of the 1st day. 1290 ± 256 ng/ml/hr increased after the 24‐day nitrazepam treatment, to 3617±202 ng/ml/hr and after the 61‐day treatment to 3379±321 ng/ml/hr. The mean maximum concentration (Cmax), 343±69 ng/ml/hr, increased to 727±52 ng/ml/hr, respectively.
Effect of Chlorpromazine on Ion Transport Induced by Cholera Toxin, Cyclic AMP and Cyclic GMP in Isolated Mucosa from Hen Intestine
Authors: Lönnroth Ivar , Munck Bjarne G.
Published: July 2010

Abstract: The isolated short circuit mucosa of chicken colon was established as an in vitro model for studies of the pathophysiology of diarrhoea and the mechanism of action of antidiarrhoeic drugs. Cholera toxin, 10−7 M, added to the mucosal side of the preparation, caused in a delayed reaction a pronounced increase of short circuit current (Isc). Cyclic AMP, which mediates the effect of cholera toxin (when added serosal) induced an immediate rise of Isc. Half maximal reaction was achieved at 3 mM cyclic AMP and maximal at 7 mM. The increase of Isc corresponded to the increase in the flux of chloride from serosa to mucosa. Unlike cyclic AMP, cyclic GMP almost equally stimulated sodium and chloride transport from serosa to mucosa, while the effect on Isc of the two nucleotides was additive. Chlorpromazine, which effectively reverses diarrhoea in cholera patients, totally normalized Isc after treatment with either cholera toxin, cyclic AMP or cyclic GMP. This reduction was achieved by a specific stimulation of transport of chloride from mucosa to serosa. The effect occurred also without previous treatment of the tissue with secretagogues (cholera toxin, cyclic nucleotides). No change in mucosal resistance was induced by chlorpromazine or cyclic GMP while it was reduced by cyclic AMP.
Radioimmunoassay for Atropine and l‐Hyoscyamine
Authors: Virtanen R. , Kanto J. , Iisalo E.
Published: July 2010

Abstract:A simple, specific and sensitive radioimmunoassay is described for atropine (dl‐hyoscyamine) and l‐hyoscyamine. Antiserum was obtained from rabbits immunized with an immunogen prepared by coupling l‐hyoscyamine to human serum albumin. By using3H‐atropine as tracer, the assay can detect atropine and l‐hyoscyamine concentrations down to 9 nmol/1 (2.5 ng/ml)in a 0.1 ml serum or plasma sample, The recovery of atropine was near 100% when the drug was added at different concentrations to normal, pooled human plasma. Atropine and l‐hyoscyamine are recognized equally well by the antibodies, but some other structurally related drugs (homatropine, scopolamine) and atropine hydrolysis products (tropine, tropic acid) do not interfere. The usefulness of the method in pharmacokinetic studies was shown by assaying atropine concentrations in serial serum samples from two patients, who were given 1.3 mg atropine in connection with anaesthesia. A biexponential serum decay curve was demonstrated in both cases with a very rapid distribution phase (t 1/2 0.63 and 1.38 min.) and a much slower elimination phase (t 1/2A 1.86 and 2.09 hrs.).
Competitive Blockade of α‐Adrenergic Receptors in Rat Heart by Prazosi
Authors: Skomedal T. , Osnes J.‐B. , Øye I.
Published: July 2010

Abstract: Pheiiykphriiie (PE) in presence of propranolol evokes an α‐adrenergic inotroyic response in rat heart. The time course of this response is characterizcd by a transient ducrease in maximal developed tension (Tmax) subcontrol levels (negative phase of the inotropic response) followed by an increase which reaches maximum after 4–5 min. (positive phase of the inotropic response). Prazosin (PRZ), a selective α1‐receptor blocker. inhibited preferentially the positive phase of the inotropic response and displaced the dose‐responsecurve of PE to the right in nanomolar concentrations, indicating a competitive mechanism of inhibition. Phentolamine, a non‐selrctive α‐blocker. blocked both the negative and the positive phase olthe inotropicresponse toabout the same degree. PRZ appears to be a competitive α‐adrenergic antagonist with high affinity in rat heart. Two populations of α‐adrenergic receptors may he present: one stirnulatory (α1) iind one inhibitory
Reduced Fluoride Sensitivity of Liver Cells from Rats Chronically Exposed to Fluoride
Authors: Hongslo Jan K. , Hongslo Cecilie F. , Hasvold øystein , Holland Roy I.
Published: July 2010

Abstract:The fluoride sensitivity, determined as effect on protein synthesis (incorporation of14C‐leucine), of liver and kidney cells in suspension culture was explored. The cells were freshly prepared by collagenase perfusion from rats given drinking water with or without addition of 100 p.p.m. (5.26 mM) fluoride for 9–28 weeks. The fluoride sensitivity of the liver cells from rats given fluoridated water for more than 9 weeks was decreased compared to cells from control rats, whereas the fluoride sensitivity of the kidney cells from fluoride exposed and control rats appeared similar. Fluoride resistance (i.e. decreased sensitivity) may thus develop also in cellsin vivo. When exposed to 3 mM NaF for 1 hour the intracellular concentration of fluoride in liver cells from fluoride exposed and control animals was similar.
The Modifying Effect of Autonomic Blockade on Digitoxin‐induced Changes in Monophasic Action Potential and Refractoriness of the Right Ventricle of the Dog Heart
Authors: Amlie Jan P.
Published: July 2010

Abstract:The aim of the present investigation was to study the modifying effect of autonomic blockade with atropine plus propranolol and atropine alone on the electrophysiologic response to digitoxin during an observation period of 8 hours. Twenty‐five pentobarbital‐anaesthetised Labrador dogs were used. Monophasic action potentials from the right ventricle (V‐MAP) were obtained by the suction electrode technique. Pacing and programmed electrical stimulation were used to determine heart rate independent changes in repolarisation times and the effective (V‐ERP) and the functional (V‐FRP) refractory periods. The dogs were divided into three groups and all dogs got digitoxin (2.0 mg) intravenously during 5 min. Fourteen dogs were given digitoxin without blockade, while 5 dogs were pretreated with propranolol 0.5 mg/kg plus atropine 0.05 mg/kg every hour for 8 hours and 6 dogs with atropine in the same dose and with the same interval. Digitoxin alone increased 50 and 90% repolarisation times 2–4 hours after injection of the drug. During autonomic blockade digitoxin induced a shortening of action potential duration, and thus digitoxin interacts with autonomic transmitters resulting in prolongation of action potential duration. The “direct” effects of digitoxin, the action potential shortening effect, the decrease in membrane responsiveness (i.e. V‐ERP/50% repolarisation time) reached a maximum 2–3 hours after injection of the drug.
Effect of GABA Analogues on Blood Pressure and Central GABA Metabolism in the Rat
Authors: Persson B. , Henning M.
Published: July 2010

Abstract:Gamma aminobutyric acid (GABA) and different GABA analogues were examined for their cardiovascular actions and their influence on striatal dopamine (DA) levels and GABA accumulation after aminooxyacetic acid (AOAA). Gamma hydroxybutyric acid (GHBA) and baclofen caused hypertension and tachycardia after systemic as well as intracerebroventricular administration, while the opposite was true for GABA and muscimol. The hypertension after GHBA and baclofen was not reduced by picrotoxin or bicuculline and was not influenced by varying GABA levels by 3‐mercaptopropionic acid (3‐MPA)or AOAA. GHBA and muscimol but not baclofen reduced GABA accumulation induced by AOAA. Picrotoxin in a subconvulsive dose increased GABA accumulation and antagonized the inhibition after GHBA or muscimol. Bicuculline and a moderate dose of picrotoxin tended to decrease GABA accumulation by themselves and if anything augmented the effects of GHBA and muscimol. GHBA and baclofen but not muscimol in combination with AOAA increased DA levels, which was not prevented by picrotoxin or bicuculline. We conclude that the cardiovascular actions of GHBA and baclofen are probably not mediated by mechanisms identical to those of muscimol or exogenous GABA. In view of the biochemical results their actions would however be compatible with a concept of different GABA receptors.