bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell‐Mediated Immunity Caused by Beryllium Compounds
Authors: Sakaguchi Sanae , Sakaguchi Takehiro , Nakamura Iwao , Kudo Yoshiro
Published: March 2009

Abstract: Cells of spleen and lymph nodes were obtained from mice subcutaneously injected with BeCl2 once a week over a 6‐week period. These cells were washed twice in cold phosphate‐buffered saline and suspended at a final concentration of 2 × 107 cells in 1 ml of buffer. Subsequently, 0.5 ml of the suspension was injected into normal mice intravenously (passive transfer). The findings of the experiments using these mice are summarized as follows: (1) The footpad reaction test was performed 24 hrs after passive transfer. The mice receiving spleen cells or lymph node cells from mice sensitized with BeCl2 developed significant footpad swelling 24 and 48 hrs after challenge of BeCl2 as the antigen. (2) After passive transfer with sensitized spleen cells or lymph node cells the ears of the mice were painted with 7% BeCl2 in ethyl alcohol. Ears of these mice showed significant swelling as compared with those of controls. (3) The migration of peritoneal cells from mice receiving spleen or lymph node cells from sensitized mice was inhibited when tested in medium containing the antigen of BeCl2. From our present experiments, it was suggested that the beryllium sensitizing ability was related to active as well as passive cell‐mediated immunity.
Pharmacokinetics and Metabolism of Metioprim in Pigs and Goats
Authors: Nielsen Poul , Gyrd‐Hansen N. , Olsen Carl‐Erik , Xia Wenjiang
Published: March 2009

Abstract: The pharmacokinetics and metabolism of metioprim (MTP) have been studied after intravenous administration of a single dose of 5 mg/kg b.wt. to pigs (n=4) and 10 mg/kg b.wt. to goats (n=5). Kinetic parameters were calculated using a two‐compartment open model. The elimination half‐life was much shorter in goats (23$pL4 min.) than in pigs (169$pL17 min.). The apparent volume of distribution exceeded 1.0 l/kg b.wt. in both species indicating accumulation in tissues. Pigs excreted the major part of the dose (86$pL9%) in urine and only a small part (9$pL3%) in faeces, while the goats excreted almost equal amounts in urine (55$pL5%) and faeces (38$pL4%). Metabolism played the major role in elimination of MTP. Of the 80% of the dose excreted in urine within 24 hrs in pigs unchanged MTP made up 8%, metioprim sulfoxide 64% and O‐desmethyl‐MTP 8%. Metioprim sulfoxide was also the major metabolite in goats, but in this species another demethylated metabolite – metioprim sulfonic acid – was formed. Goats excreted 49$pL7% of the dose in urine within 24 hrs of which unchanged MTP made up less than 1%, while metioprim sulfoxide accounted for about 35% and metioprim sulfonic acid for approximately 14%. Metabolites isolated from urine were identified by NMR‐spectroscopy combined with EI, FAB or 252Cf plasma desorption mass spectrometry.
Glucuronidation of the Enantiomers of E‐10‐Hydroxynortriptyline in Human and Rat Liver Microsomes
Authors: Dumont Etienne , Von Bahr Christer , Perry Thomas L. , Bertilsson Leif
Published: March 2009

Abstract:Conjugation of racemic E‐10‐hydroxynortriptyline (E‐10‐OH‐NT) with glucuronic acid was studied in the liver microsomal fraction of rats and humans. The diastereomeric glucuronides of E‐10‐OH‐NT were resolved and quantitated by HPLC. Only the (+)‐enantiomer was glucuronidated in liver microsomes from humans. Rat liver microsomes catalyzed the formation of both glucuronides. Phenobarbital pretreatment of rats increased the glucuronidation of both enantiomers about five‐fold. The formation rate of (+)‐E‐10‐OH‐NT glucuronide varied from 5.5 to 33.2 pmol/mgxmin, in microsomes from 13 humans. High activity was found in individuals previously treated with pentobarbital. Inhibition experiments with human liver microsomes showed that amitriptyline is a potent competitive inhibitor of (+)‐E‐10‐OH‐NT glucuronidation. p‐Nitrophenol, paracetamol and 2‐hydroxydesipramine also inhibited this reaction.
Formation of a Quaternary N‐Glucuronide of Amitriptyline in Human Liver Microsomes
Authors: Dahl‐Puustinen Marja‐Liisa , Bertilsson Leif
Published: March 2009

Abstract:Amitriptyline N‐glucuronide was isolated from urine of a patient treated with therapeutic doses of amitriptyline. The glucuronide was hydrolyzed by hot alkaline treatment and, to a lesser degree, by treatment with β‐glucuronidase. A method for the direct measurement of amitriptyline glucuronide by HPLC was developed. Human liver microsomes were shown to glucuronidate amitriptyline in the presence of UDPGA, and the activity varied 7‐fold among microsomes from 13 different human livers. The glucuronidation of amitriptyline was inhibited by p‐nitrophenol but not by morphine. E‐10‐hydroxynortriptyline, a major metabolite of amitriptyline, had only a slight inhibitory effect on the glucuronidation of amitriptyline. No significant correlation was found between the glucuronidation of amitriptyline and that of E‐10‐hydroxynortriptyline in the microsomes studied.
Mechanisms of Absorption of Inorganic Mercury from Rat Small Intestine. I. Solvent Drag Effect on Absorption of Inorganic Mercury
Authors: Endo Tetsuya , Nakaya Shozo , Kimura Ryohei
Published: March 2009

Abstract: A correlation of mercury absorption with water absorption was investigated by using the perfusion of rat small intestine with buffers containing 10−4 M HgCl2. With a decrease in the osmolarity of the buffers or with increases in the sodium ion and urea concentrations in the buffers, absorption of water and mercury and accumulation of mercury in the intestinal tissue increased, and the increases in mercury absorption and accumulation were found to correlate with the increase in water absorption. Both the decrease in osmolarity and the increase in sodium ion concentration increased mercury accumulation in the epithelial cell after the perfusion. But these changes did not alter the mercury distribution in subcellular fractions. The results suggest that the increase in water absorption due to the hyptonicity or the increase in concentration of sodium ion or urea increases the mercury absorption and accumulation in the epithelial cell without change in the distributional pattern of mercury in the cell.
The Disposition of Chloramphenicol in Colostrum‐Fed and Colostrum‐Deprived Newborn Pigs
Authors: Martin K. , Wiese B.
Published: March 2009

Abstract:The pharmacokinetics of chloramphenicol (CAP) were studied in four colostrum‐deprived and 4 colostrum‐fed newborn piglets after an intravenous bolus dose of CAP, 77 μmol kg−1(25 mg kg−1). The elimination half‐lives in the colostrum deprived piglets had a tendency to be longer (17.2 ± 3.9 hrs) than in the colostrum‐fed piglets (12.7 ± 1.1 hrs) and in both groups they were considerably longer than reported in older pigs. The long half‐lives of CAP in the newborn pigs were a reflexion of very low clearance (Cl) values, 0.0391 ± 0.007 and 0.0512 ± 0.007 1 kg−1hr−1, in the two groups, while the volume of distribution was of the same size in the two groups, 0.9549 ± 0.247 and 0.9411 ± 0.211 1 kg−1. The protein binding of CAP in pooled piglet plasma was concentration dependent, 53–45%, (P<0.001) in the concentration range 31–232 μM (10–75 μg ml−1) and the binding degree was significantly higher in plasma from colostrum deprived piglets, 53.0 ± 0.8% compared to plasma from colostrum fed, 47.5 ± 1.3% (P<0.01).
Properties of the Inotropic Response in Rat Papillary Muscles to the Dihydropyridine “Ca‐Channel Activator” BAY K 8644
Authors: Skomedal Tor , Schiander Iwona , Aass Halfdan , Osnes Jan‐Bjørn
Published: March 2009

Abstract:The aim of the present study was 1) to characterize qualitatively the positive inotropic effect of the Ca‐channel activator BAY K 8644 and to compare this response to response‐types with known and different relationship to the cyclic AMP (cAMP) system (e.g. responses elicited through α‐ and β‐adrenergic receptor stimulation) and 2) to study the effect of simultaneous muscarinic cholinergic stimulation upon the BAY K 8644 response in order to further evaluate the role of the cAMP system in this response. The responses were evaluated in isolated, electrically paced, isometrically contracting papillary muscles from rat heart. Isometric tension (Tmax), rate of rise and decline of tension (first derivative = T′) and rate of transition from tension rise to tension decline (negative part of second derivative = T”) were recorded. In the presence of the α1‐adrenergic receptor blocker prazosin (10−7mol/l) and the β‐adrenergic receptor blocker timolol (10−6mol/l), the positive inotropic effect of 1.7 × 10−6mol/l BAY K 8644 developed rather slowly with a time to half maximal effect of about 4 minutes. Qualitatively the response was characterized by an almost proportional (“symmetrical”) increase in all parts of the contraction‐relaxation cycle with a small prolongation of time to peak tension and of the duration of the whole cycle. This response contrasted sharply with the cAMP‐dependent response to β‐receptor stimulation (β‐type response with shortening of time to peak tension), but was very similar to the cAMP‐independent response to α‐receptor stimulation (α‐type response). Additional cholinergic muscarinic stimulation by carbacholdid notcounteract the effect of BAY K 8644, but rather increased the inotropic response. It is concluded that both the qualitative characteristics of the BAY K 8644 response and the effect of simultaneous cholinergic stimulation upon this response are those expected for a cAMP‐independent response. The results also support the assumption that the response type can be used as a first step in classifying whether an inotropic agent is dependent or independent upon activation of the cAMP system.
7‐Ethoxycoumarin and 7‐Ethoxyresorufin O‐Deethylase in Human Foetal and Adult Liver: Studies with Monoclonal Antibodies
Authors: Pacifici G. M. , Park S. S. , Gelboin H. V. , Rane A.
Published: March 2009

Abstract:The 7‐ethoxycoumarin and 7‐ethoxyresorufin O‐deethylase activities were investigated in the microsomal fractions from 5 human adult and 3 foetal livers and 5 human foetal adrenals. The enzyme activity expressed as pmol/min. per mg microsomal protein was higher with 7‐ethoxyresorufin as substrate in all investigated specimens with average values (± S.E.M.) of 74 ± 27, 13 ± 3 and 12 ± 1 in adult and foetal livers and foetal adrenals, respectively. Monoclonal antibodies raised against 3‐methylchloranthrene or phenobarbital induced rat liver cytochrome P‐450 were investigated with respect to their inhibiting effects on the rate of O‐deethylation of both substrates in human adult liver. Only the monoclonal antibody against the 3‐methylcholanthrene induced cytochrome P‐450 inhibited the O‐deethylation of 7‐ethoxyresorufin to 64 to 79 percent of control values. The other antibody had no effect on this or the other O‐deethylase activity. Thus, the 7‐ethoxyresorufin O‐deethylase is partly catalyzed in human adult liver by a cytochrome with an epitope that is recognized by the monoclonal antibody against 3‐methylcholanthrene induced rat liver cytochrome P‐450. With foetal liver the low activity of the enzyme became unmeasurable in the presence of this antibody.
The Effect of Different Storage Conditions on the Chemical Stability, Laxative Effect and Acute Toxicity of Sennoside Solutions
Authors: Lainonen Heli , Marvola Martti , Hietala Pentti , Parviainen Tuuli
Published: March 2009

Abstract: This paper investigates the effect of different storage conditions on the chemical stability, laxative effect and acute toxicity of sennoside solutions. The variables in storage conditions were pH, time and temperature (room temperature or 100°). The chemical stability of sennosides in aqueous solutions was found to be pH‐dependent, with the best stability at pH 6.5 (t90· =8.4 months) and the poorest at pH 8.0 (t90· = 2.5 months). Two years of storage at room temperature did not reduce the laxative potency in mice, regardless of the pH. After 4.25 years of storage the potency declined in alkaline solutions only. The degradation products with laxative potencies are chemically unknown. The acute toxicity of sennoside solutions increased with time during storage, the acid solution being more toxic than either the neutral or alkaline ones.
Enhanced in Vivo‐Lipid Peroxidation Associated with Halothane Hepatotoxicity in Rats
Authors: Younes Maged , Heger Bruno , Wilhelm Klaus‐Peter , Siegers Claus‐Peter
Published: March 2009

Abstract: To study the role of lipid peroxidation in halothane‐induced hepatic damage, ethane exhalation by rats exposed to 1% halothane for 1 hour was determined under normoxic (21% O2) and hypoxic (6% O2) conditions. The effects of microsomal enzyme induction by phenobarbital and/or glutathione depletion on this parameter of in vivo lipid peroxidation were studied. To assess the degree of liver damage, serum activities of liver specific enzymes (glutamate‐pyruvate‐transaminase, GPT, and sorbitol dehydrogenase, SDH) were measured 3 hrs after the end of exposure. Besides, liver content of thiobarbituric acid‐reactive materia! was estimated as a further parameter of lipid peroxidation. Enhanced rates of lipid peroxidation over basal levels were only seen under conditions leading to hepatic damage, i.e. phenobarbital induction and hypoxia. The highest rate of lipid peroxidation was observed after depletion of hepatic glutathione in addition to microsomal enzyme induction and hypoxia. Deferrioxamine, diethyldithiocarbamate and (+)‐catechin inhibited in vivo lipid peroxidation, but only (+)‐catechin suppressed halothane‐hepatoxicity. These results indicate that halothane‐induced hepatic damage is associated with an enhanced rate of lipid peroxidation, but this might not be the only mechanism of halothane toxicity.
Relationship between Forskolin and Calcium‐Calmodulin Stimulation of Rat Cerebral Cortex Adenylate Cyclase: Enzyme Activation Modulates Substrate (MgATP) Affinity
Authors: Uhlén Staffan , Wikberg Jarl E. S.
Published: March 2009

Abstract:In membranes prepared from the rat cerebral cortex EGTA 0.4–100 μmol/1 was found to dose‐dependently inhibit adenylate cyclase activity, both during basal conditions and when the cyclase activity had been stimulated with 10 μmol/1 forskolin. Addition of calcium 2–30 μmol/1 (in excess of EGTA) totally prevented the inhibition induced by EGTA, both in the absence and presence of forskolin. These data are consistent with the notion that in the absence of EGTA the rat cortex adenylate cyclase is considerably stimulated by endogeneous calcium‐calmodulin. The data also show that stimulation with endogenous calcium‐calmodulin is more than additative with that of forskolin indicating an action on identical cyclase units. The kinetics of the rat cortex adenylate cyclase for its substrate (MgATP) was also investigated. Activation of the cyclase with endogenous calcium‐calmodulin, induced a marked increase in the Vmaxof the enzyme and a concomitant almost 2‐fold increase in the Km. Stimulation with 10 μM forskolin also induced a marked increase in the Vmaxas well as an almost 3‐fold increase in the Km. A combination of the two stimulants caused a further increase in Vmaxas well as Km; the Vmaxbeing increased more than 17‐fold and the Kmbeing increased 3.5‐fold over the basal. The data indicates that both calcium‐calmodulin and forskolin induces a similar type of activation of the adenylate cyclase which is associated with a lowered affinity for its substrate.
Pharmacokinetics of Verapamil and Norverapamil in Patients with Hypertension: A Comparison of Oral Conventional and Sustained Release Formulations
Authors: Jørgensen N. P. , Walstad R. A.
Published: March 2009

Abstract: A double blind, double dummy, randomized cross‐over pharmacokinetic study comparing verapamil 120 mg, conventional tablets administered twice daily and verapamil 240 mg sustained release tablets once daily was performed in 12 patients with essential hypertension. After frequent blood sampling, analyses of verapamil and norverapamil were made with high pressure liquid chromatography. The absorption rate of the sustained release formulation was significantly slower than for the conventional formulation. Also the mean residence time was significantly longer for the sustained release tablet. It can be concluded that verapamil sustained release tablets meet with the following requirements for these formulations: (1) a slower absorption with an acceptable bioavailability relative to conventional tablets (89%); (2) no initial high peak concentration; (3) little fluctuation in the plasma concentration compared to the conventional formulation; (4) no differences in the elimination half lives for the two formulations; (5) maintenance of a therapeutic plasma level for a longer period of time than for the conventional formulation; (6) no increase in unwanted side effects.
Lithium‐Induced Morphological Changes in the Rat Kidney at Different Levels of Urine Flow
Authors: Ottosen Peter D. , Jacobsen Niels O. , Christensen Sten
Published: March 2009

Abstract: Lithium treated rats become poluyric and at the same time develop pronounced dilatations of distal tubular segments and characteristics enzyme histochemical changes. In the present study we have compared lithium‐polyuric Wistar rats with lithium treated rats in which the polyuria was prevented either by administration of a vasopressin analogue or by water restriction. The kidneys were studied using enzyme histochemistry and light microscope morphometry. The characteristic lithium induced changes were present in all groups irrespective of the presence or absence of polyuria. It is concluded therefore, that the morphological and enzyme histochemical changes are induced by the lithium ion per se and not by the accompanying polyuria.
Increased Duration of Dopamine Receptor Antagonist‐Induced Effects on both Behaviour and Striatal Dopamine Turnover by Repeated Testing in Rats
Authors: Hillegaart Viveka , Ahlenius Sven , Fowler Christopher J. , Magnusson Olle
Published: March 2009

Abstract:The present results show that the effects on striatal dopamine (DA) turnover of a single dose of the DA receptor antagonists haloperidol or raclopride in the rat, are dependent on the activity level of the animal during treatment. Thus, animals tested for treadmill locomotion 30 and 60 min. after injection display an increased striatal DA turnover at 90 or 120 min. (raclopride and haloperidol, respectively) compared with control animals which were administered the same dose of the DA antagonist, but which did not have the treadmill tests. The relevance of these findings with respect to individual differences in clinical response and occurence of side effects as well as the reported difficulties in obtaining good correlations between plasma levels and clinical response with DA‐receptor blocking antipsychotic drugs are discussed.
Effects of Temperature on thein VitroBinding of3H‐Raclopride to Rat Striatal Dopamine‐D2Receptors
Authors: Hall Håkan , Wedel Ilse , Sällemark Maria
Published: March 2009

Abstract:The influence of temperature on thein vitrobinding of3H‐raclopride to rat striatal dopamine‐D2receptors was investigated. The KD‐values obtained in Scatchard plots were approximately 1.6 nM at temperatures between 15° and 30°. At 37° the KD‐value was found to be 3.0 nM, indicating a lower affinity without affecting the number of the receptors (Bmax). The rate of association of3H‐raclopride to the receptors was decreased with decreasing temperatures, and at 6° more than 150 min. incubation was needed to reach the steady state level. From the association constants, the activation energy of the binding reaction was calculated to be 80 kJ/mol. The driving forces of the binding reaction was suggested to be a change in entropy at temperatures up to 30° but a change in enthalpy at 37°.
Allosteric Stabilization of3H‐N‐Methylscopolamine Binding in Guinea‐Pig Myocardium by an Antidote against Organophosphate Intoxication
Authors: Jepsen Kerstin , Lüllmann Heinz , Mohr Klaus , Pfeffer Joachim
Published: March 2009

Abstract:W84 (hexamethylene‐bis‐[dimethyl‐(3‐phthalimidopropyl)‐ammonium bromide]) protects overadditively against an organophosphate‐intoxication when applied in combination with atropine. Further experimental evidence led to the hypothesis that W84 exerted an allosteric effect on muscarinic acetylcholine receptors. In order to investigate the action of W84 on the receptor level, binding studies with3H‐N‐methylscopolamine were performed in homogenized and intact guinea‐pig myocardium. For sake of comparison three bispyridinium oximes were included, i.e. Uno3 (trimethylene‐bis‐[4‐hydroxyiminomethyl‐pyridinium] dibromide mono‐2,6‐dichlorobenzylether), obidoxime, and TMB4. In cardiac membrane suspensions, all compounds inhibited3H‐NMS‐binding after 2 hrs of incubation concentration‐dependently by reducing its affinity, whereas leaving the number of binding sites unaltered. However, with increasing concentrations W84 suppressed3H‐NMS‐binding less than expected for a competitive antagonist. Kinetic studies revealed that W84 did not only slow the association of3H‐NMS, but additionally retarded its dissociation over the entire range of concentrations that inhibited3H‐NMS‐binding. At ImM, W84 augmented the half life time of the3H‐NMS‐receptor complexes from a control value of 4 min to more than 120 min. The stabilization of the radioligand‐receptor complexes is indicative of an allosteric effect of W84. Obidoxime, TMB4 and Uno3 at low concentrations acted like competitive inhibitors of3H‐NMS‐binding. From 10‐−5M onwards, Uno3 retarded3H‐NMS‐dissociation concentration‐dependently. It is concluded that the effect of bisquaternary compounds on3H‐NMS‐association and‐dissociation is mediated via binding to two separate sites, i.e. the muscarinic receptor site and an allosteric effector site, respectively. Also in intact beating left atria, W84 retarded3H‐NMS‐dissociation concentration‐dependently. The stabilizing effect of W84 on antagonist‐receptor complexes may explain the overadditive protective action exerted by the combination of atropine and W84 against organophosphate intoxication.
Determination of Thyroxine Release in Vivo: A Simple, Specific and Sensitive Method in Mice
Authors: Hedner P. , Bengtsson H. I. , Ahren B.
Published: March 2009

Abstract: When thyroid hormone secretion in vivo was studied by the release of 125I from thyroid to blood after TSH in mice preloaded with the isotope, only 54.4 ± 2.0% (± SE) of plasma 125I was butanol extractable, indicating low specificity for thyroid hormones. To improve specificity plasma 125I was bound to anti‐T4 rabbit antibodies and precipitated with goat antirabbit serum. The intraassay coefficient of variation was 2.5%, and anti‐T4 bound radioactivity correlated well with that extractable with butanol (r = 0.95, P < 0.001). The effect of 40–1000 μU TSH intravenously in mice pretreated with 1 μg T3 3 times during 2 days to suppress endogenous TSH was evaluated 2 hrs after the injection of TSH by 1) conventional radioimmunoassays of total and free stable T4 in plasma (no preloading with 125I), 2) total blood 125I in mice preloaded with 125I, and 3) anti‐T4 bound 125I in plasma in mice preloaded with 125I. Stable T4 increased with TSH doses of 70 μU or higher, but the slope was low and the relation between error variance and slope did not permit a useful bioassay. Total blood 125I responded significantly to 40 μU TSH and showed a favourable relation between error variance and slope, but the specificity may be questioned. Anti‐T4 bound 125I in plasma also responded significantly to 40 μU TSH and showed a very good relation between error variance and slope. The new technique of measuring anti‐T4 bound radioactivity seems to combine the specificity of radioimmunoassay with a precision and sensitivity well comparable to that of the conventional radioiodine release technique.
Inhibition of Cyclic AMP Production by α2‐Adrenoceptor Stimulation in the Guinea‐Pig Spinal Cord Slices
Authors: Uhlén Staffan , Wikberg Jarl E. S.
Published: March 2009

Abstract:In spinal cord slices isolated from guinea‐pig and preincubated with3H‐adenine, 0.3–30 μM forskolin induced a dose‐dependent increase in the content of3H‐cAMP, the maximal increase being about 8‐fold. The selective α2‐adrenergic agonist UK‐14,304 (10 μM) reduced both the basal and the forskolin stimulated levels of3H‐cAMP by 18–32%. Dose response curves of the effect of UK‐14,304 on cAMP production in the spinal cord slices, stimulated with 3 μM forskolin, showed an IC50 of 37 nM and a maximally inhibitory effect of 27%. A number of other α2‐adrenergic agonist (clonidine, guanfacine, B‐HT 920 and B‐HT 933) also inhibited the forskolin stimulated3H‐cAMP production; clonidine and guanfacine being almost equipotent with UK‐14,304, but their maximal inhibitory effects being only about 6–7%. B‐HT 920 and B‐HT 933 were less potent and their maximal inhibitory effects about 16–21%. The dose response curve of UK‐14,304 on inhibition of forskolin stimulated cAMP production was shifted almost 50‐fold to the right by 0.3 μM yohimbine. Prazosin (0.3 μM) did not affect the UK‐14,304 dose resonse curve. It is concluded that α2‐adrenoceptor stimulation mediates inhibition of cAMP production in the guinea‐pig spinal cord.
Pharmacodynamics and Pharmacokinetics of Enprofylline and Theophylline in the Isolated Rabbit Heart
Authors: Nielsen‐Kudsk Jens Erik , Askholt Jan
Published: March 2009

Abstract: The direct effects of theophylline and enprofylline, a new anti‐asthma xanthine derivative without adenosine receptor blocking action, were studied in the isolated, spontaneously beating rabbit heart. At increasing concentrations from 2 × 10−5–5 × 10−4 M both drugs produced increases in heart rate up to 143% and 162% and in contractility up to 135% and 147% from control values (100%), respectively. At concentrations higher than 10−3 M contractures and heart block occured. Enprofylline showed a potency about 2.3 times higher than theophylline. Coronary flowrate did not increase. Myocardial oxygen consumption was moderately increased by the drugs. The myocardial pharmacokinetics showed two‐compartment characteristics for both drugs. Half‐times of the two phases of accumulation were for theophylline 0.28 and 0.98 min. and for enprofylline 0.31 and 0.78 min. The terminal disposition half‐time for enprofylline was, however, 2.7 times higher than that of 0.91 min. for theophylline, apparently due to a stronger binding of the former drug intracellularly. Both xanthines accumulated against a concentration gradient showing myocardial tissue‐perfusion liquid ratios of about 2.9 for theophylline and 3.7 for enprofylline. The drugs seem to exert their primary action on sarcolemmal binding sites which probably are unrelated to adenosine receptors.
Screening for Drugs Blocking Acetylcholine‐Activated Ion Channels and Local Anaesthetics with the Isolated Chick Biventer Cervicis Preparation
Authors: MacDonald Ewen
Published: March 2009

Abstract: A convenient method for screening for drugs that block acetylcholine‐activated ion channels, using the isolated chick biventer cervicis preparation is described. Since most of these drugs can only gain access to their site of action when the ion channel is in the open configuration, their effects are potentiated by prior treatment of the preparation with neostigmine. By preventing hydrolysis of acetylcholine, neostigmine enhances the possibility that ion channels will be in the open configuration. Potentiation of their neuromuscular blocking effects by neostigmine is apparently specific for drugs acting this way, other non‐depolarizing neuromuscular blocking drugs are usually antagonized by neostigmine. The chick biventer cervicis preparation also contains a second set of accessible ion channels, the so‐called voltage‐gated channels in the nerve axons which are the site of action of local anaesthetic compounds. It has been observed that addition of local anaesthetics to the bathing solution causes an increase in the potential required to elicit indirect muscle contractions i.e. they induce a shift to the right of the voltage‐response curve, a property which may be included in screening procedures with the isolated chick biventer cervicis preparation.
Acute Tolerance to and Distribution of Hexobarbital in Relation to Depth and Duration of Anaesthesia in Rats
Authors: Bolander Hans G. , Wahlström Göran
Published: March 2009

Abstract:The development of acute tolerance to hexobarbital was investigated with an EEG‐threshold method in rats. Hexobarbital was infused in a tail vein and the effect was monitored either by continous EEG‐recording (using the criterion “silent second”) or by continous observation. Anaesthesia was maintained at the level of “the silent second” for periods of up to 120 min. After different time intervals the last infusion period to the EEG‐criterion was followed by decapitation and samples from blood, brain, muscle and fat were analysed for hexobarbital content. Brain concentrations at the EEG criterion increased and were notable after 10 min. but statistically significant at 30 min. when a 40% increase in concentration was needed to reach the criterion. Another group of rats kept at a lower level of anaesthesia (i.e. the righting reflex) showed a slight but not always significant increase in concentration when measured in different parts of the brain at “silent second”. The dose of hexobarbital needed to maintain anaesthesia for intervals up to 120 min. increased almost linearly with time. Analysis of serum, muscle and fat tissue showed that concentration in fat tissue increased linearly during this whole interval and served as the final depot in redistribution. Muscle tissue shows an increase up to 60 min. but a very small increase thereafter, which is consistent with a function as temporary storage compartment.
No Effect of Roxithromycin on Pharmacokinetic or Pharmacodynamic Properties of Warfarin and its Enantiomers
Authors: Paulsen O. , Nilsson L.‐G. , Saint‐Salvi B. , Manuel C. , Lunell E.
Published: March 2009

Abstract: The macrolide antibiotics are metabolized by cytochrome P‐450 enzymes in the liver and interactions with similarly metabolized compounds have been described. Simultaneous treatment with erythromycin and warfarin is known to decrease warfarin clearance and prolong prothrombin time. Roxithromycin (RU 28965), a new erythromycin derivative with improved pharmacokinetic properties, might then, because of structure similarity, be expected to interact with warfarin. In 21 healthy volunteers, the effect of orally administered roxithromycin (150 mg b.i.d.) on warfarin steady‐state kinetics, and the effects of warfarin on roxithromycin kinetics, were investigated in a double‐blind, randomized study versus placebo. Since the warfarin enantiomers, R‐ and S‐warfarin have both different potency and different metabolism, the ratio between the enantiomers with and without roxithromycin, was also determined. In this study, mean AUC for warfarin increased slightly from day 14 of warfarin treatment to day 28, but no difference was found between the roxithromycin group and the placebo group, and no change appeared in the ratio between the warfarin enantiomers. A moderate increase in dosage was needed to maintain hypocoagulability during warfarin medication, but there was no difference between the roxithromycin group and the placebo groups, respectively. In addition, roxithromycin kinetics appeared to be unaffected by warfarin treatment.
The Interaction of Cations with Activity of Soluble Protein Kinase C from Mouse Brain
Authors: Saijoh K. , Inoue Y. , Katsuyama H. , Sumino K.
Published: March 2009

Abstract:The interaction of some cations with the enzymatic activity of soluble protein kinase C was determined in order to elucidate whether protein kinase C can be activated by other metal cations besides Ca2+. Protein kinase C was activated by Ca2+and Sr2+having EC50 values of nearly 10 μM and 200 μM, respectively. Ba2+likewise activated protein kinase C but was less potent. Co2+, Ni2+and Mn2+had no activating effects on the activity in the absence of Ca2+, but was slightly reduced in the presence of Ca2+(0.5 mM). Cations with ionic radii close to Ca2+(0.99 Å) inhibited the activity irrespective of the absence or presence of Ca2+. The order of potency is as follows: Hg2+> Cd2+∼ Cu2+≫ Sm3+> Tb3+> La3+, Pb2+and Zn2+, which showed a high affinity to SH‐groups, as well as Hg2+, Cd2+and Cu2+, which also inhibited the activity. Thus, among the ions investigated, the alkaline‐earth ions Sr2+and Ba2+could be substituted for Ca2+, irrespective of ionic radii. The serious environmental pollutants such as Hg2+, Cd2+or Pb2+impaired the activity of protein kinase C probably due to SH‐blocking.
Prenatal Methylazoxymethanol Treatment Potentiates d‐Amphetamine‐ and Methylphenidate‐Induced Motor Activity in Male and Female Rats
Authors: Archer Trevor , Fredriksson Anders , Sundström Erik , Luthman Johan , Lewander Tommy , Söderberg Ulf , Jonsson Gösta
Published: March 2009

Abstract: The effects of the stimulant drugs, d‐amphetamine and methylphenidate, upon the motor activity of male and female off‐spring of pregnant rats, treated on gestation day 15 with the antimitotic agent methylazoxymethanol (MAM, 25 mg/kg) were studied in four experiments. Cortical and striatal hypoplasia induced by prenatal administration of MAM resulted in increased concentrations of catecholamines in those regions. Administration of d‐amphetamine and methylphenidate caused significant increases in motor activity; this effect was markedly potentiated in the MAM‐treated rats, both the male and female off‐spring. Thus, the locomotion and total activity parameters showed similar, but not identical, drastic increases in behaviour induced by the stimulant drugs as a result of the prenatal MAM treatment whereas for the rearing parameter a lesser potentiation by the MAM treatment was observed. This potentiation of the excitatory effects of the stimulant compounds upon the behavioural parameters is interpreted in terms of a relative increase in the density of catecholaminergic terminals in the forebrain regions of the central nervous system. The present results are discussed with regard to the utility of prenatal MAM treatment as a possible animal model for certain neurological disorders.
Disordered Catecholamine Release in Pigs Susceptible to Malignant Hyperthermia
Authors: Häggendal Jan , Jönsson Lennart , Johansson Göran , Bjurström Sivert , Carlsten Johan
Published: March 2009

Abstract: Pigs, crossbreeds of Swedish Landrace and Yorkshire, females and castrated males about 6 months old, were exposed to experimental stress. The pigs were either considered normal or shown to be susceptible to develop malignant hyperthermia when tested with halothane at about 6 weeks of age (stress‐susceptible pigs). The stress was of the restraint type, produced by two different myorelaxant agents, the depolarizing succinylcholine or the non‐depolarizing pancuronium. The blood levels of the catecholamines (CA) noradrenaline (NA) and adrenaline (A) were measured during the stress. The severity of myocardial cell necrosis observed 1 to 2 days after the stress was morphologically graded. In normal pigs the levels of NA during the stress and the degree of myocardial cell necrosis were about the same after both succinylcholine and pancuronium. In stress‐susceptible pigs, however, succinylcholine produced very high NA and A levels and severe heart lesions, whereas after pancuronium the NA and A levels were rather low and the heart lesions significantly reduced when compared to those after succinylcholine‐induced stress. After pretreatment with dantrolene intravenously the succinylcholine‐induced stress only induced slightly increased blood CA levels and no signs of myocardial cell necrosis in pigs susceptible to develop malignant hyperthermia. Dantrolene, an efficient drug in treatment of malignant hyperthermia, probably acts by interfering with release of calcium from the sarcoplasmic reticulum in skeletal muscles. The results indicate that peripheral sympathetic neurones in MHS pigs also react abnormally, probably due to defective calcium turn‐over.
The Influence of Morphine and Naloxone on Plasma Oxytocin Concentration in the Rat
Authors: Grell Stig , Christensen Jens Dencker , Fjalland Bjarne
Published: March 2009

Abstract: Subcutaneous injections of morphine decrease the plasma oxytocin level significantly in both normohydrated rats and rats dehydrated for 24 hrs. This effect of morphine is naloxone‐reversible. Injections of naloxone increase the plasma oxytocin level in a time dependent manner, when the oxytocin system is stimulated by dehydration, but have no effect on basal oxytocin level. This observation indicates liberation of an endogenous opioid, during stimulation of the neurohypophysis, leading to inhibition of the oxytocin secretion. A discrepancy in the time course between the plasma oxytocin enhancing effect and the morphine reversing effect of naloxone is observed. On the basis of this observation two different opioid receptors are suggested to be involved in the effect of naloxone on the neurohypophysis.
Progesterone, some Progesterone Derivatives and Urinary Digoxin‐Like Substances from Pregnant Women in Radioimmuno‐ and 86Rb‐Uptake Assays of Digoxin
Authors: Vinge Ellen , Helgesen‐Rosendal Sonja , Bäckström Torbjörn
Published: March 2009

Abstract: Progesterone and some derivatives were tested in a radioimmunoassay (RIA) of digoxin and in a bioassay measuring the 86Rb‐uptake into red blood cells as an index of Na+, K+‐ATPase activity. The digitalis‐like activity of the hormones was compared with that found in chromatographic fractions of material extracted from the urines of pregnant women at term. Progesterone at concentrations > 10−6 M cross‐reacted in the RIA, and at 10−3 M it decreased 86Rb‐uptake by 18%. The anaesthetic progesterone derivates 5α‐pregnane‐3α‐ol‐20‐one and 5α‐pregnane‐3,20‐dione crossreacted to a lesser degree in the RIA and lacked effect in the bioassay. Similar results were obtained with pregnandiol‐glucuronide, the major urinary metabolite of progesterone. In contrast, several fractions of the urinary material had significant effects in both assays. It is concluded that the digitalis‐like activity of progesterone is not coupled to properties associated with its anaesthetic effects. Furthermore, although progesterone may account for a part of the endogenous digoxin‐like substances in serum of neonates and pregnant women, neither progesterone proper nor pregnandiol‐glucuronide explains the great amount of digoxin‐like substances found in the urines.
The Effect of Furosemide on Vascular Smooth Muscle is Influenced by Plasma Protein
Authors: Andreasen F. , Christensen J. Heslop
Published: March 2009

Abstract:The effect of furosemide on vascular smooth muscle was studied on segments of rabbit blood vessels. Furosemide (20 μg/ml) induced small (3–4%) decreases in resting tension whereas nitroglycerin (0.5 μg/ml) induced decreases from 8 to 13%. The addition of albumin (45 g/l) abolished the furosemide response whereas the nitroglycerin response was unaffected. Similarly the pronounced effect of nitroglycerin on electrically evoked contractions was unaffected by the presence of albumin whereas the furosemide effect was weakened by albumin. The biologically determined free fraction of furosemide increased with increasing drug concentrations from 13% at 16 μg/ml to 35% at 256 μg/ml.
Halothane Induced Hepatic Necrosis in Rats: The Role ofin VivoLipid Peroxidation
Authors: Knights Kathleen M. , Gourlay Geoffrey K. , Gibson Robert A. , Cousins Michael J.
Published: March 2009

Abstract:Hepatic damage was induced in phenobarbitone pretreated male Fischer 344 rats by the administration of 1 % halothane in 14% oxygen for either 1 or 2 hours. Ethane production during the exposure period was not significantly different between the halothane and non‐halothane exposed groups. Animals were sacrificed 1, 2, 6 and 24 hrs from commencement of anaesthesia and the hepatic microsomal fraction analyzed for diene conjugates, lipid hydroperoxides, total lipid content and fatty acid composition. Animals exposed to halothane and sacrificed at 2 and 24 hrs had significantly elevated levels of diene conjugates (P < 0.05), while lipid hydroperoxide concentration and serum alanine aminotransferase increased in only those animals sacrificed at 24 hrs. Alterations in total lipid content and hepatic microsomal fatty acid composition were not observed in animals sacrificed after 1 and 2 hrs. A significant reduction in total lipid and arachidonic acid content occurred only in those animals sacrificed 24 hrs after exposure, however a concomitant increase in the saturated fatty acid fraction was not observed. It is proposed that alterations in fatty acid compositionin vivoand evidence of lipid peroxidation occur as a result of cell death rather than an initiating event in halothane induced hepatic necrosis in rats.
Changes in Renal Function in Cadmium‐Intoxicated Rats
Authors: Kim Y. K. , Choi J. K. , Kim J. S. , Park Y. S.
Published: March 2009

Abstract: Changes in renal function, Na+‐K+‐ATPase activity and PAH transport system in the kidney cortex were studied in rats treated with cadmium. Subcutaneous injections of CdCl2 (2 mg Cd/kg · day) for 16 days induced a marked polyuria and a hyposthenuria. These changes were accompanied by increase in urinary protein, glucose, urea, calcium, phosphate, chloride and potassium excretions. The change in urine flow was proportional to the change in total osmotic solute excretion. Creatinine excretion and TcH2O remained unchanged. Na+ excretion was not increased, but the Na+‐K+‐ATPase of renal cortex was significantly inhibited. PAH uptake by renal cortical slices was markedly attenuated in Cd‐treated rats. The Vmax for active PAH influx was drastically reduced, but the Km was not changed. The passive influx and efflux of PAH across the basolateral membrane and the renal tissue oxygen consumption were not apparently altered in Cd‐treated animals. These results indicate that 1) the nature of Cd‐induced polyuria and hyposthenuria is an osmotic diuresis induced by proximal tubular rejection of various substances, and 2) the mechanism of impaired renal PAH excretion in Cd‐treated animals is a loss of organic anion carriers in proximal tubular basolateral membranes.
Distribution of 14C‐Ochratoxin A in the Mouse Monitored by Whole‐Body Autoradiography
Authors: Fuchs Radovan , Appelgren Lars‐Erik , Hult Karl
Published: March 2009

Abstract: The tissue distribution of 14C‐labeled ochratoxin A was studied in mouse using whole‐body autoradiography. The distribution was followed for 18 days after one single intravenous injection of 5 μCi/animal, corresponding to 160–230 ng toxin/g body weight. Very long persistence of 14C‐ochratoxin A in the circulation was noticed and the toxin was detected in the blood even after 18 days when the experiment was finished. The radioactivity in the kidney was unequally distributed with a slightly higher concentration in the inner cortical and medullary parts. This was seen from 24 hrs and on after injection. Very high concentrations of radioactivity were found in the bile of treated animals. The radioactivity extracted from several sections was chemically characterized with thin‐layer chromatography and was found to represent 14C‐ochratoxin A.
Mechanisms of Absorption of Inorganic Mercury from Rat Small Intestine. II. Composite Effects of pH and Halide Ions on Transport of Mercuric Chloride into Isolated Brush Border Membrane Vesicles in Rats
Authors: Endo Tetsuya , Nakaya Shozo , Kimura Ryohei
Published: March 2009

Abstract: Composite effects of pH and halide ions on the transport of HgCl2 into brush border membrane vesicles (BBMV) were investigated in rats. BBMV were incubated for 10 min. in buffer solution at different pH containing 10−4 M HgCl2. The increase in pH increased the uptake of Hg by BBMV as a result of the increase in transport of Hg into intravesicular space and decrease in binding of Hg to BBMV. The isotonic displacement of NaCl in the buffer solution by LiCl or KCl did not change the uptake of Hg at each pH. The displacement of NaCl by mannitol increased the uptake of Hg at each pH, while the displacement by NaBr or Nal decreased the uptake and diminished the increasing effect of pH on the uptake of Hg. These changes in uptake of Hg due to the displacement were mainly ascribed to the changes in transport of Hg. These results suggest that the increase in pH mainly increases the transport of HgCl2 as a result of the conversion to hydroxide forms of Hg such as Hg(OH)Cl and Hg(OH)2, and Cl−, Br− and I− act as the competing ions with OH− and decrease the transport of Hg.
Acute and Subacute Effects of Diazepam on Human Performance: Comparison of Plain Tablet and Controlled Release Capsule
Authors: Mattila Marja
Published: March 2009

Abstract: The psychomotor performance of 9 healthy volunteers was measured in a randomized, double‐blind, cross‐over manner after single doses (Day 1) and one‐week maintenance (Day 8) with diazepam given in uncoated tablets (DZ) or in controlled‐release capsule (DZ‐CR). The performance was measured objectively (simulated driving, digit symbol substitution, Maddox wing, flicker fusion, tapping rate) and subjectively (visual analogue scales, questionnaires) at baseline and 1.5 and 3 hrs after the intake of DZ 15 mg, DZ‐CR 20 mg, or placebo. The maintenance dose for diazepam was 10 mg daily. Subjective, but not objective, responses to placebo were evident on Day 1, but not on Day 8. As expected, DZ impaired most objective test performances on Day 1, the strongest effects seen at 1.5 hr. Subjectively it caused drowsiness and impaired performance. These effects were weaker but still significant on Day 8. DZ‐CR produced less effects on both objective and subjective measurements on Day 1. It was about inert on Day 8, yet exophoria and subjective muzziness increased after the last dose; the subjects did not experience their performance as impaired. Measurements of plasma benzodiazepine concentrations confirmed the different pharmacokinetic profiles of DZ and DZ‐CR due to different rates of absorption, yet characteristic accumulation of diazepam and its active metabolites during maintenance was seen with both formulations. The results suggest that DZ‐CR capsule with less acute psychomotor impairment and steady pharmacokinetic profile would well suit to the treatment of anxiety for longer periods.
Cyanide‐Induced Injury to the Isolated Perfused Rat Liver
Authors: Younes Maged , Strubelt Otfried
Published: March 2009

Abstract: In order to study the events that follow cyanide‐induced inhibition of oxidative metabolism and produce cellular injury, isolated, haemoglobin‐free perfused rat livers from fasted rats were exposed to KCN (100 mg/l). KCN reduced the oxygen consumption of the livers by about 80%. Hepatotoxicity was evident by a marked release of enzymes (LDH, SDH) and of glutathione (mainly GSSG) into the perfusate, by a depletion of hepatic glutathione and by an accumulation of calcium in the liver. Cyanide‐induced hepatotoxicity could be prevented completely by feeding the rats before preparing the liver as well as by addition of fructose to the perfusate of fasted livers. Both treatments resulted in an increased energy supply from anaerobic glycolysis as evidenced by a large release of lactate + pyruvate into the perfusate. The toxic actions of cyanide were markedly attenuated by deferrioxamine as well as by allopurinol. These antitoxic actions occurred without changes in anaerobic glycolysis. Ommission of calcium from the perfusate, however, did not influence cyanide toxicity. Thus, energy supply from anaerobic glycolysis seems to be sufficient for the basic functions of the liver to occur, when oxidative metabolism is inhibited by cyanide. The effects of deferrioxamine and allopurinol indicate the involvement of radical intermediates and/or Fe2+ in cyanide‐induced cellular toxicity. An influx of calcium from the extracellular to the intracellular space is not involved in cyanide‐induced hepatocellular injury.