bluuebunny/crossref_metadata_2025 huggingface dataset:
Clonidine Increases the Rate of Blood Pressure Recovery from Splanchnic Nerv e Stimulation
Authors: Petersen Erling N.
Published: July 2010

Abstract Clonidine reduced both the pithed rat heart rate and blood pressure responses to low frequency sympathetic nerve stimulation. Marked shortening of the blood pressure response but not of the heart rate or of the responses to injected noradrenaline was found. This shortening effect was independent of the number of impulses in the train (4‐120 impulses) and of the impulse frequency. It lasted for more than 1 hour and was found to affect only the late part of the pressor decay curve. Nerve stimulations at 2 Hz simulating bursts of different periodicity in the splanchnic nerves showed that the cumulation of the blood pressure between bursts was affected only when these were applied at intervals of more than 10 sec. The effect could not be influenced by antagonists to several known transmitters, by ligation of the renal arteries or by adrenalectomy and does not seem to be mediated by pre‐ or postjunctional a receptor stimulation.
Prekallikrein Activator and Kallikrein in Acetone‐ and Kaolin‐activated Rat Plasma
Authors: Berstad Jan
Published: July 2010

Abstract Activation of plasminogen‐free rat citrated plasma (RCPL‐P) with acetone/kaolin yielded BAEe‐esterase activities of 0.6‐0.8 U/ml. Gel filtration demonstrated one single peak of BAEe‐esterase activity (mol. wt. approximately 135000) with a kininogenase‐esterase ratio (3.3) close to that known for human plasma kallikrein (2.7). Similarly activated rat citrated plasma (RCPL) revealed on gel filtration an additional esterase peak (mol. wt. approximately 47,000) with a low kininogenase‐esterase ratio (0.3), and should accordingly not be used for a BAEe‐esterase assay of rat plasma kallikrein. Acetone activation of RCPL‐P and of RCPL yielded prekallikrein activator (PKA) activities which were about doubled by treatment with kaolin to 1.9‐2.1 and 3.5‐4.2 PKA‐U/ml respectively. Gel filtration of acetone‐activated RCPL‐P or RCPL revealed two peaks of PKA activity, mol. wt. approximately 110,000 corresponding to activated factor XII (XIIa), and mol. wt. approximately 33,000 corresponding to XII fragments (XIIf). Kaolin‐treatment of acetone‐activated RCPL‐P, but not of RCPL, caused an extensive fragmentation of XII, to the 4‐6 times more active XIIf. The lower yield of PKA‐activity in acetone/kaolin‐activated RCPL‐P, as compared with activated RCPL, seems to be due to the absence of a factor of significance for the activation of factor XII, which is not plasmin, plasma kallikrein, or high molecular weight kininogen.
Interaction Studies between Three Antidepressant Drugs (Chlorimipramine, Imipramine and Zimelidine) and Noradrenaline, Tyramine and Vagal Stimulation on the Heart Rate and Blood Pressure in Dogs
Authors: Johnsson C. , Lundborg P. , Welin‐Fogelberg I.
Published: July 2010

Abstract Anaesthetized Beagle dogs were given increasing intravenous doses of imipramine, chlorimipramine or zimelidine. At each dose interval the interference of the drug administered with the effects on blood pressure and heart rate of vagal stimulation, NA injection and tyramine injection was investigated. Also, the in vitro uptake of 5‐HT into platelets after in vivo administration to unanaesthetized dogs of 5 mg chlorimipramine or 5 mg zimelidine was studied. Chlorimipramine and zimelidine were found to be about equipotent as regards 5 HT‐uptake into platelets after in vivo administration. Imipramine and chlorimipramine potentiated the effects of NA after the 2 mg/kg dose. Imipramine but not chlorimipramine interfered with the effects of tyramine after the 4 mg/kg dose. Zimelidine did not interfere with either NA or tyramine at any dose level studied (maximal cumulative dose 62 mg/kg). The effect of vagal stimulation was significantly inhibited after 8 mg/kg (cumulative dose 14 mg/kg) of imipramine and 16 mg/kg (cumulative dose 30 mg/kg) of chlorimipramine and zimelidine, respectively. It is concluded that zimelidine in comparison with imipramine and chlorimipramine has no or at most a slight effect on peripheral adrenergic neurones. It has less pronounced anticholinergic properties than imipramine but is about equipotent to chlorimipramine in this respect.
Intravenous Glucose Tolerance in Lithium Treated Rats
Authors: Vendsborg Per
Published: July 2010

Abstract A method for performing intravenous glucose tolerance tests in anaesthetized rats was developed, and factors influencing basal glucose tolerance was investigated. Glucose tolerance increased with increasing weight and body temperature, but decreased with fasting. Lithium administration increased glucose tolerance. The increase varied with the dose and the time interval between administration and glucose tolerance test. There was an immediate increase in glucose tolerance after lithium administration, which lasted under special conditions up to 24 hours. The duration was depending on the dose given and the fasting state of the animal.
Acute and Subacute Effects of Diazepam on Psychomotor Skills: Interaction with Alcohol
Authors: Palva E. S. , Linnoila M. , Saario I. , Mattila M. J.
Published: July 2010

Abstract Effects of diazepam and alcohol on psychomotor skills were measured in two trials. In the first one, 200 healthy students volunteered for a double‐blind single‐dose study. Three doses of diazepam (5, 10 and 20 mg) and alcohol (0.5, 0.8 and 1.2 g/kg) were used alone and combined to construct dose‐response graphs. All doses of alcohol impaired divided attention while co‐ordinative skills were impaired by the 1.2 g/kg dose. Diazepam alone did not impair reactive or co‐ordinative skills whereas the combinations of diazepam and alcohol did so. To further elucidate the subacute effects, a double‐blind randomized study was conducted administering 2 and 10 mg of diazepam t.i.d. for two weeks to 18 healthy volunteers. The psychomotor tests were performed on the 7th and 14th days of drug administration, and 0.5 g/kg of alcohol was given on either day. Diazepam 2 mg, alone or with alcohol, did not differ from placebo. 10 mg of diazepam slightly increased reaction times but not reaction mistakes, and impaired both co‐ordination and attention. Alcohol did not enhance diazepam effects. We suggest that a development of tolerance to diazepam may compensate the deleterious interaction of the agents found in acute studies.
Salivary Secretion Evoked by H80/62, (±)‐1‐(4‐hydroxyphenoxy)‐3‐isopropylamino‐2‐propranol, a New β1‐selective Adrenoceptor Agonist
Authors: Ekström Jørgen
Published: July 2010

Abstract H80/62, recently introduced as a β1‐selective adrenoceptor agonist, caused a long‐lasting flow of saliva from parotid and submaxillary glands of the rat. The effect of H80/62 was prevented by propranolol or a β1‐selective blocker. The drug did not exert its effect via the sympathetic postganglionic nerves; and it was not taken up by the neuronal amine pump. Sympathetically decentralized or denervated glands acquired a supersensitivity of the postjunctional type to H80/62.
Inhibition of Brain Synaptosomal Uptake of Choline by Some 2‐Carboxamidostrychnine Derivatives with Muscle‐relaxant Properties
Authors: Eckernäs Sven‐åke , Bohlin Lars , Sahlström Lena
Published: July 2010

Abstract: Some 2‐carboxamido derivatives of strychnine with a peripheral muscle‐relaxant effect in vivo and in vitro were tested for their ability to inhibit choline (Ch) uptake into mouse brain synaptosomes. A non‐competitive inhibition of the high affinity Ch uptake by strychnine and some of its derivatives was observed.
Transfer of Lorazepam and its Conjugate Across the Human Placenta
Authors: Kanto J. , Aaltonen L. , Liukko P. , Mäenpää K.
Published: July 2010

Abstract: The concentrations of lorazepam and its conjugate were determined in maternal venous serum, in umbilical vein and artery serum, and in amniotic fluid after a single 2 mg intramuscular and 2.5 mg oral maternal administration. During normal delivery (2 mg intramuscular injection) and caesarean section (2.5 mg orally) both the unconjugated and conjugated forms of lorazepam were found in the umbilical circulation and amniotic fluid. The serum protein unbound fraction was 14.0±4.8 (S.D.) % in maternal circulation and 20.8 ±3.1% in umbilical circulation. Generally, lorazepam was a useful anxiolytic agent during normal delivery and as a sedative on the night before caesarean section.
Plasma Induced Biotransformation of Thymoxamine and its Kinetics
Authors: Nielsen‐Kudsk Folmer , Jakobsen Preben , Magnussen Ib
Published: July 2010

Abstract: Thymoxamine, 6‐acetoxythymol‐2‐dimethylaminoethyl ether, is a competitive α‐adrenoceptor blocking agent used as a vasodilator in the treatment of peripheral vascular disorders. The plasma half‐life of the drug in vivo is very short. In vitro experiments showed that thymoxamine had a half‐life in human plasma of about only 1 min. By using the compound as a substrate in increasing concentrations from 5–320 μg/ml in the presence of a fixed, low concentration of plasma (0.1 % v/v) at pH 7.4 and 37° a hyperbolic correlation was found between the concentration of thymoxamine and the intial rate of formation of the involved reaction product, which was determined by HPLC. A linearized Michaelis‐Menten plot indicated an enzymatic biotransformation. A Km‐value of about 0.115 μmol ml−1 and a Vm‐value of about 0.0037 μmol ml−1 min.−1 were found. Physostigmine, neostigmine and cinchocaine inhibited the biotransformation competitively. This indicated that plasma cholinesterase was the enzyme responsible. The metabolite was identified as desacetylthymoxamine by HPLC, spectrophotometry and direct inlet mass spectrometry.
The Effect of Immediate and Delayed Treatment with 2,3‐Dimercaptopropane‐l‐sulphonate on the Distribution and Toxicity of Inorganic Mercury in Mice and in Foetal and Adult Rats
Authors: Wannag Axel , Aaseth Jan
Published: July 2010

Abstract The distribution and excretion of mercury were studied in mice and rats given a single injection of HgCl2 combined with chelation treatment. BAL‐sulph (2,3‐dimercaptopropane‐l‐sulphonate) given intravenously (500 μmol SH/kg) to mice 24 hrs after the mercury injection (2.0 μmol Hg/kg) reduced the kidney Hg‐level significantly, while NAPA (N‐acetyl‐DL‐penicillamine) and BAL (2,3‐dimercaptopropanol) did not. Severe kidney damage with oliguria was observed in pregnant as well as in non‐pregnant rats after injection of 5μmol/kg of HgCL2. The gross pathological changes could be avoided with immediate treatment with BAL‐sulph (500μmol SH/kg), and such treatment protected against the oliguric reaction. Treatment delayed for 24 hrs reduced the renal Hg‐levels significantly, but was ineffective in preventing the kidney damage. This indicates that irreversible changes might have occurred in kidneys cells at this time. The Hg‐levels in the brain were either unchanged or lowered in animals given BAL‐sulph treatment. BAL‐sulph is supposed to act by chelation of Hg++, particularly in the extracellular space. The complexes formed appears to be rapidly excreted by healthy kidneys. Mercury poisoning with severe renal damage is, however, associated with a block in urinary Hg‐excretion. The poisoned animals responded on the BAL‐sulph treatment with a substantial raise of faecal mercury excretion.
Purification of GABA on Small Columns of Dowex 50W; Combination with a Method for Separation of Biogenic Amines*
Authors: Carmona Euridice , Gomes Cecilia , Trolin Gustaf
Published: July 2010

Abstract Elution of GABA has been included in the method for separation of biogenic amines on small Dowex 50W columns described by Atack & Magnusson (1978). After extraction with perchloric acid and neutralization to pH 3.0, the sample is passed through the column. 5‐HIAA might thereafter be eluted as described by Lindqvist (1971). After washes with water and 8 ml of a 0.025 M sodium citrate buffer pH 4.5, GABA is eluted in 3 ml of a 0.05M sodium citrate buffer pH 5.3–5.4. The elution of tryptophane and the above mentioned amines can thereafter be performed. The recovery of GABA from the column is 100%. Silica thin‐layer chromatography of the GABA eluate gives only one ninhydrine positive spot with a Rr value identical to GAB A standard. When the GABA eluate from a whole brain and spinal cord is run on an automatic amino acid analyser, only one peak is detectable, eluted in the same position as GABA standard. Fluorescence analysis of the GABA eluate gives similar values if a) ninhydrine. b) acetylacetone plus formaldehyde or c) fluorescamine is used to form the flurophore. The GABA values are identical whether the samples reacted with ninhydrine are diluted with water or copper tartrate. The GABA concentrations found in some parts of the rat brain are of the same order of magnitude as reported by other authors.
Bioavailability and Related Pharmacokinetics in Man of Orally Administered L‐5‐Hydroxytryptophan in Steady State
Authors: Magnussen I. , Nielsen‐Kudsk F.
Published: July 2010

Abstract The bioavailability of orally administered L‐5‐hydroxytryptophan in steady state was investigated at four increasing multiple dose levels in five patients suffering from various myoclonic disorders. An L‐aromatic amino acid decarboxylase inhibitor was co‐administered in all the experiments. The disposition pharmacokinetics of the amino acid had been established in the same patients in preceding intravenous single dose experiments. The finding of a direct proportionality between the size of the oral dose level of L‐5‐hydroxytryptophan and the corresponding areas under the plasma concentration curves within a dosage interval at steady state strongly indicates dose independent, linear pharmacokinetics of the compound. The systemic availability of L‐5‐hydroxytryptophan exhibited an interindividual range of 47–84%, with a mean value of 69.2% ±4.7 S.E.M. The absorption took place at a rather slow rate as judged from times of 1.8 to 3.3 hours elapsing from administration of the compound until occurance of the maximum measured plasma concentrations. Transitory nausea and vomiting were only recognized in few instances during the gradual building up of increasing steady state levels of L‐5‐hydroxytryptophan in the patients, and the importance of a slow initiation of therapeutical treatment with the amino acid is emphasized.
Concentration of Serotonin Metabolites in the Cerebrospinal Fluid from Alcoholics before and during Disulfiram Therapy
Authors: Beck O. , Borg S. , Holmstedt B. , Kvande H. , Skröder R.
Published: July 2010

Abstract: The levels of 5‐hydroxytryptophol and 5‐hydroxyindoleacetic acid were measured in the cerebrospinal fluid before and after one week of disulfiram treatment (400 mg/day) from ten male hospitalized alcoholic patients. The disulfiram treatment induced elevated (P<0.001) levels of 5‐hydroxytryptophol. The levels were higher than in a control group, both before (P <0.01) and after (P< 0.001) the treatment. No effects on the levels of 5‐hydroxyindoleacetic acid were noted. The results indicate an altered serotonin metabolism in alcoholics, which is further potentiated by disulfiram treatment.
Activation of Factor XII in Rat Plasma: Protection by Benzamidine of the Cofactor Function of High Molecular Weight Kininogen
Authors: Briseid Kjell , Berstad Jan
Published: July 2010

Abstract: Factor XII has been assayed as kaolin‐activated prekallikrein activator in rat citrated plasma pretreated with acetone (Briseid et al. 1978 & 1979; Briseid & Berstad 1979). In the present work benzamidine added during blood collection increased the extent of activation by a factor of 6. Rat high molecular weight kininogen (HMWK) added to acetone‐treated citrated plasma likewise increased the activation, providing evidence of the protection by benzamidine of the cofactor function of HMWK. All cofactor capacity was retained after the removal of the kinin part of HMWK. Experiments carried out with plasminogen‐free plasma showed that plasmin could hardly be the factor responsible for the destruction of HMWK. The stoichiometric factor XII concentration‐effect curve obtained by diluting acetone‐treated rat plasma with acetone‐treated human factor XII deficient plasma showed that factor XII is present in functional excess, the concentration of HMWK deciding the extent of activation. By diluting acetone‐treated rat plasma with buffer, HM WK concentration‐effect curves were obtained which were approximately linear over a range of 0.03–0.40 μg (bradykinin equivalents) per ml kaolin incubate. No further activation of factor XII was obtained at 0.80 μg/ml.
Methyl Mercury Binding Substances from the Brain of Experimentally Exposed Squirrel Monkeys (Saimiri Sciureus)
Authors: Winroth G. , Carlstedt I. , Karlsson H. , Berlin M.
Published: July 2010

Abstract: Squirrel monkeys were given a single subtoxic dose of 203Hg‐labelled methyl mercuric hydroxide. After three weeks the brains were dissected out, homogenized and separated into particulate and soluble fractions by ultracentrifugation. The soluble fractions were further separated into high molecular weight and low molecular weight components by ultrafiltration. The major part (75%) of the radioactivity was associated with the particulate fraction while high molecular weight compounds in the soluble fraction accounted for 16%. The remainder (9%) was bound to glutathione.
Effect of Repeated Doses of Hydroflumethiazide on Renal Excretion of Electrolytes and Uric Acid in Healthy Subjects
Authors: Brørs O. , Jacobsen S. , Foss O. P. , Aakvaag A.
Published: July 2010

Abstract: Urinary excretion of electrolytes and uric acid was investigated in six healthy subjects during repeated oral administration of 100 mg hydroflumethiazide (HFT) daily for seven days, and related to urinary thiazide excretion. Mean 24 hr‐urinary excretion of sodium and chloride increased 100% (P<0.02) after the first HFT‐dose, whereas 24 hr‐excretion values were at control level after the fourth and seventh doses. Mean 24 hr‐urinary excretion of potassium was increased by 31% after the first HFT‐dose (P<0.05) and by 47% after the fourth dose (P <0.05). After HFT was discontinued, mean urinary excretion rates of sodium and chloride dropped to 30% and that of potassium to 70% of control. In the state of fluid deficiency and elevated aldosterone concentration, there was a significant positive correlation between log excretion rate of HFT and excretion rate of sodium (r=0.68, P<0.002) calculated from excretion data 0–6, 6–12, and 12–14 hrs after the seventh dose. After the first dose of HFT, sodium excretion was also significantly correlated to log excretion rate of HFT (r=0.86, P<0.001) but was probably influenced by other factors as well. Mean serum concentration of uric acid increased significantly, but mean 24 hr‐urinary excretion of uric acid was constant during HFT‐treatment.
Reduction of Zearalenone to Zearalenol in Female Rat Liver by 3α‐Hydroxysteroid Dehydrogenase
Authors: Olsen M. , Pettersson H. , Kiessling K.‐H.
Published: July 2010

Abstract: The distribution of the zearalenone reducing activity was investigated in liver fractions obtained by differential centrifugation of liver homogenate from adult female Sprague Dawley rats. The zearalenone reducing enzyme was identified as 3α‐hydroxysteroid dehydrogenase. At least two multiple forms occur of the enzyme with different subcellular locations and pH‐optima. The activity was localized in the microsomes with NADH as coenzyme and in both microsomes and cytosol with NADPH.
Cigarette Smoke Inhibits Contractile Responses of Isolated Hamster Stomach Strip to Prostaglandin E2
Authors: Toivonen Hannu , Uotila Pekka
Published: July 2010

Abstract: Cigarette smoke inhibited the contractile responses of isolated hamster stomach strips to prostaglandin E2. Filtration of visible particles from the smoke did not abolish this inhibitory action. Buffer solution, which had been bubbled with cigarette smoke, was not inhibitory. Carbon dioxide was a potent inhibitor, but it could be removed from the smoke without any clear effect on the inhibitory action of the smoke. Carbon monoxide was also a potent inhibitor but slightly weaker than cigarette smoke. It is suggested that the main inhibitor in the cigarette smoke could be carbon monoxide but its action was modified by other factors.
On the Mechanism of Inhibition of Rat Fat Cell Adenylate Cyclase by Lithium
Authors: Thams Peter , Geisler Arne
Published: July 2010

Abstract: This study aimed to elucidate the mechanism by which Li+ inhibits adenylate cyclase (AC) in vitro. It was found that Li+ inhibited the norepinephrine‐ (NE) and the fluoride‐ (F) stimulated AC activities of rat fat cell ghosts at Li+ concentrations above 10 mM. The basal enzyme activity was unaffected even at 80 mM of Li+. Li+ inhibited the NE‐induced AC activity in a mainly non‐competitive way, but the inhibitory effect decreased with increasing concentrations of NE. The inhibition by Li+ of both NE‐ and F‐‐stimulated AC activities was antagonized by Mg2+. The Mg2+ antagonism of the Li+‐induced inhibition of the NE‐stimulated AC activity was independent of the NE concentration. Furthermore, Ca2+, inhibiting AC activity by a Mg2+ antagonism, abolished the inhibitory effect of Li+. It is suggested that Li+ affects both the Ka of NE and the Vmax of AC through 1) an inhibitory action of LiATP3‐ at the catalytic site of AC or 2) an inhibitory action of Li+ at an allosteric Mg2+ site of AC.
Clinical Pharmacology of Dichlorvos
Authors: Slomka M. B. , Hine C. H.
Published: July 2010

Abstract Polyvinyl resin formulation pellets (V‐3 and V‐12) containing dichlorvos were administered to male volunteers in single doses up to 32 mg/kg and repeated doses up to 16 mg/kg/day for up to three weeks. The cholinesterase activity depressions following single doses were dose related. Following multiple doses, the plasma cholinesterase activity was maximally depressed at all dose levels and the RBC cholinesterase activity depression was dose related.
Equilibrium Dialysis for Determination of Protein Binding of Imipramine – Evaluation of a Method
Authors: Kristensen Christian Bruun , Gram Lars F.
Published: July 2010

Abstract: A range of methodological problems associated with equilibrium dialysis for serum or plasma protein binding assay of a weakly basic drug, imipramine, in man has been carried out in order to establish a reliable procedure for large scale studies. Freezing of serum samples did not change the binding significantly, but a slight tendency towards increased binding in samples stored for 30 days was found. Protein binding was significantly higher in serum than in heparinized or citrated plasma, whereas there was no significant difference between plasma obtained by use of heparin or citrate as anticoagulant. There was a linear correlation between temperatue (25–42°) and binding such that binding decreased 0.1% per centigrade increase in temperature. Increase in pH resulted in increase in binding (0.6% per 0.1 unit pH). Equilibrium between serum and buffer phase was obtained within 5–6 hrs. The changes following osmotic equilibration necessitated volume corrections of about 4–5% after 5–6 hrs, and 20–25% after 16–20 hrs (overnight experiments). With this correction the free fraction estimate remained constant for 26 hrs. Application of small volumes in the dialysis chamber may make the volume correction difficult and inaccurate. The use of Tris‐Ringer buffer gave free fraction values about 20% higher (absolute values of free fraction) than that with phosphate buffer. With different imipramine concentrations a constant degree of binding was found at “therapeutic” levels, whereas a significantly decreased binding was found at a concentration of 1000 ng/ml. Control of these methodological factors is a prerequisite for obtaining reproducible and valid results, and authors should give more details on methodology in this field.
Effects of Long‐term Ethanol Consumption on Rat Peritoneal Macrophages
Authors: Mørland Berit , Mørland Jørg
Published: July 2010

Abstract: Rats were fed an all liquid diet for 7–8 weeks. One group received 35% of the calories as ethanol while the other group was pair‐fed carbohydrates. Peritoneal macrophages prepared from ethanol treated rats had lower phagocytosis via the Fc‐receptor and reduced viability in the presence of endotoxin, but their lysosomal enzyme activities measured (β‐glucuronidase, cathepsin D, acid phosphatase and acid DNase) were not different from controls.
Effects of Ethanol on Locomotor Activity in Rats of Different Ages
Authors: Lamble Robert , Rydberg Ulf
Published: July 2010

Abstract: Using male Sprague‐Dawley rats of different ages, simple motor activity was measured over three 4 min. runs in a square open field after ethanol (EtOH, 2 g/kg, intraperitoneally) or saline. The different groups consisted of 12 animals whose mean ages was 20, 40 and 60 days. Motor activity and blood ethanol levels were measured at 30, 60 and 120 min. after injection. Blood ethanol levels (measured after each run) decreased from 1st to 3rd run in 20 and 40 day groups and increased from 1st to 2nd run in the 60 day group, before decreasing. Activity data indicated: 1) decrease in motor activity the 3 runs by all saline and the 21 day EtOH groups, 2) initial lower activity induced by EtOH in all age groups, 3) lack of decrease in activity over 3 runs in 40 and 60 day EtOH groups. All saline and EtOH age groups showed within‐run decrease of activity
Survival of Neonatal Rats during Hypoxia after Monoamine Stimulating Agents
Authors: Hedner T. , Lundborg P.
Published: July 2010

Abstract: Survival of 4 days old rats exposed to 6% O2‐94% N2 was studied. Administration of L‐DOPA (100 mg/kg) or L‐5‐HTP (100 mg/kg) reduced survival during hypoxia to about 30% of controls. A further reduction of survival time was noted after combined administration of L‐DOPA and L‐5‐HTP. Administration of increasing doses of L‐DOPA or L‐5‐HTP resulted in a dose‐related decrease in neonatal survival time. After inhibition of the peripheral L‐aminoacid decarboxylase with MK‐486, L‐DOPA caused the same reduction of survival time during hypoxia as after L‐DOPA alone. Clonidine (2 mg/kg) was found to reduce hypoxic survival time to about 60%, while apomorphine had no effect compared to controls. Clonidine and apomorphine together had the same effect as clonidine alone. It is suggested that central monoamine neurotransmitters are involved in the mechanisms determining survival during neonatal oxygen deprivation.
Effects of Chlorpromazine on Fluid Transport across the Intestinal Mucosa of the Rat
Authors: Jennische Eva , Lönnroth Ivar
Published: July 2010

Abstract: The effect of chlorpromazine (CPZ) on net fluid transport in the small intestine of the rat was studied, using a ligated loop model. Given intramuscularly at 5 mg/kg, CPZ induced a 50% increase of net fluid absorption in jejunum, but had no effect in ileum. Similarly, the drug decreased net fluid accumulation induced by dibutyryl‐cyclic AMP in jejunum, but did not influence net fluid accumulation in ileum. In contrast, net fluid accumulation induced by cholera toxin was decreased by CPZ in both jejunum and ileum. Inhibition of cyclic AMP (cAMP) – which probably mediates the hypersecretion by the toxin – was also noted. These results suggest that CPZ reverses fluid transport during cholera in two ways: by a cAMP‐independent enhancement of fluid absorption in jejunum and by inhibition of the toxin‐induced cAMP‐production in jejunum as well as ileum. Each of these processes may be independently affected by pharmacological substances and subjected to neural and hormonal regulation.
No Effect of Low‐dose 1α‐Hydroxycholecalciferol Treatment on the Renal Function Deterioration Rate in Long‐term Uraemic Rabbits
Authors: Tvedegaard Erling , Ladefoged Ole
Published: July 2010

Abstract: The development of renal function during 18 weeks of oral treatment with 1α‐hydroxycholecalciferol was investigated in rabbits with surgically induced chronic renal failure. Renal function was evaluated by the serum creatinine concentration and the 51Cr‐EDTA clearance measured by the single injection technique. Three groups of uraemic rabbits on three different diets with high, medium and low content of calcium and phosphate were studied. The treatment with 0.02 μg/kg/day of 1α‐hydroxycholecalciferol did not induce statistically significant changes in the serum concentrations of calcium or phosphate. Compared to placebo 1α‐hydroxycholecalciferol did not increase the deterioration rate of renal function in any of the three groups.
Effects of the Dopamine‐β‐hydroxylase Inhibitors FLA‐57 and FLA‐63 on Ethanol Metabolism and Aldehyde Dehydrogenase Activity in Rats
Authors: Tottmar Olof , Hellström Ewa , Holmberg Kerstin , Lindros Kai O.
Published: July 2010

Abstract: In rats pretreated with the dopamine‐β‐hydroxylase (DBH)‐inhibitors FLA‐57 and FLA‐63 (60 mg/kg, intraperitoneally, for 4 and 18 hrs), no effects on the blood acetaldehyde level after ethanol administration or on the activity of the low‐Km aldehyde dehydrogenase (ALDH) in the liver were found. FLA‐63 but not FLA‐57 decreased the rate of ethanol elimination. FLA‐63 inhibited the low‐Km enzyme in vitro, but much less than the ALDH‐inhibitors disulfiram and cyanamide. FLA‐57 caused no inhibition in vitro. The results show that the previously observed suppression of ethanol intake in rats by FLA‐57 and FLA‐63 was not caused by an acetaldehyde‐mediated aversion such as during the disulfiram‐ethanol reaction.
The Distribution of 14C‐p‐tert.‐butyltoluene (TBT) Following Inhalation by the Rat: A Whole Body Autoradiographic Study
Authors: Ingebrigtsen Kristian , Walde Anna
Published: July 2010

Abstract: The distribution of [methyl‐14C] p‐tert.‐butyltoluene was studied in the rat by use of whole‐body autoradiography and liquid scintillation counting. The test substance was administered by inhalation. High concentration of radioactivity was seen in the CNS immediately after inhalation, from where it was rapidly cleared. The liver also contained much radioactivity, as well as the bile, kidneys and the praeputial glands. Increasing amounts of radioactivity were observed in the skin, adipose tissue (brown adipose tissue) and the Harderian gland with increasing survival times. There was still some radioactivity left in the animal 96 hrs after exposure. At least part of the radioactivity in the skin, liver, brown adipose tissue, the Harderian gland and the praeputial glands was found to be non‐extractable from the sections using both polar and non‐polar solvents.
Effects of Manganese on Carbohydrate Metabolism and Mitochondrial Enzymes in Rats
Authors: Shukla Girja S. , Chandra Satya V.
Published: July 2010

Abstract: The effect of daily intraperitoneal administration of Mn2+ (4 mg/kg) was investigated on the metabolism of carbohydrates and certain enzymes involved in the oxidation of glucose in the rat liver and blood at the intervals of 30, 60 and 90 days after exposure. Mn2+ had no effect on the contents of blood reducing sugars and proteins, however the levels of pyruvic and lactic acids were reduced at 60 and 90 days after the metal treatment. The contents of liver glycogen and proteins remained unaffected while pyruvic acid content was decreased in Mn2+ treated rat liver throughout the experimental period. The activities of glycogen phosphorylase and lactate dehydrogenase decreased while that of phosphoglucoisomerase and glucose‐6‐phosphatase increased in the post mitochondrial supernatant at 60 and 90 days of Mn2+ exposure. The levels of hexokinase decreased and FDP‐aldolase and fructose‐1, 6‐diphosphatase increased throughout the experimental period. The magnitude of alteration was found to be greater with the increase in the duration of Mn2+ treatment. Several of the mitochondrial enzymes in the liver were inhibited in the manganese exposed rats which may be responsible to inhibit the rate of dehydrogenation of Kreb cycle's intermediates alongwith the linked respiratory chain and eventually oxidation in the rat liver.
Pharmacokinetics and Dose Regimen of Oral Theophylline in Children
Authors: Bolme P. , Eriksson M. , Lönnerholm G. , Paalzow L.
Published: July 2010

Abstract: The pharmacokinetics of theophylline after oral administration in tablet (Oxyphyllin®) or solution (Teovent®) form was determined in 22 children 0.6–16 years of age. Four of these children also received intravenous theophylline. The absorption of theophylline both from the tablets and from the solution was rapid (mean half‐time 14.3 and 16.1 min., respectively) and almost complete. The youngest children (2–8 years) given tablets had a significantly shorter half‐time of elimination and a higher total plasma clearance than children aged 9–16 years. Adverse effects during treatment with the oral solution were studied in another 19 children. Medication was stopped by the parents of two children because of the unpleasant taste. Gastrointestinal disturbances were frequent but not serious enough to cause discontinuation of treatment. Simulations based on obtained pharmacokinetic data showed that in the average child below nine years of age oral theophylline, 6–8 mg/kg three times daily, would give plasma levels between 10 and 20 μg/ml (55–110 μmol/l) for about 60–70% of the day. A dose of 6 mg/kg four times daily would achieve such concentrations during almost 24 hrs of the day. In the average child aged 9–16 years a reduced dose of about 5–6 mg/kg three times daily would suffice to produce plasma levels of 10–20 μg/ml owing to the slower elimination of the drug in this age group. Individual titration of the dose is necessary for optimal treatment with theophylline in all age groups.
Comparison of the Effects of a New Vasodilator Pinacidil and Nifedipine on Isolated Blood Vessels
Authors: Mikkelsen Erich , Pedersen Ole Lederballe
Published: July 2010

Abstract: In isolated human crural veins studied in vitro pinacidil (0.038–380 μM) caused a concentration‐related inhibition of noradrenaline, 18 μM (NA) and 127 mM K+‐induced contractions. Pinacidil was more potent in inhibiting the NA‐contraction than that induced by K+, whereas the reverse was seen for nifedipine. At the highest concentrations greater inhibitions of the NA‐induced contractions could be obtained with pinacidil than with nifedipine. The inhibitory effect of pinacidil on the K+‐induced contractions was eliminated during a 1 hr wash‐out period. In contrast to this, the inhibitory effect of nifedipine could not be eliminated during 4 hrs repeated wash‐out. Pinacidil was completely devoid of inhibitory effect on 45Ca net influx in rat aorta, whereas nifedipine caused a significant reduction of influx. The results indicate that both pinacidil and nifedipine are effective vasodilatators in human vessels. Pinacidil seems to be more effective in NA‐induced contractions than does nifedipine. The mechanism of action of pinacidil cannot be attributed to an inhibitory effect on cellular calcium entry.
Distribution and Elimination of 14C‐Hexachlorobenzene after Single Oral Exposure in the Male Rat
Authors: Ingebrigtsen Kristian , Nafstad Inger
Published: July 2010

Abstract: The distribution and excretion of 14C‐hexachlorobenzene (14C‐HCB) after administration to rats of a single oral dose of 50 μCi 14C‐HCB per kg body weight was studied by whole‐body autoradiography and liquid scintillation counting. Radiolabeled HCB was distributed throughout the body in 2 hours. Peak levels were found at 4 hours in the liver and the brown fat and at 24 hours in the abdominal and subcutaneous fat. The highest concentrations were found in the adipose tissues, the bone marrow, the skin, the Harderian gland, the nasal mucosa, the praeputial gland, and the intestinal tract. After 90 days, substantial amounts were present only in the adipose tissue, the skin, the nasal mucosa, and the praeputial gland. Part of the radioactivity in the brown fat, the bone marrow, the praeputial gland, the adrenal gland, the liver, the blood, the kidney, the spleen, the lungs, the heart and the gastrointestinal contents was found not to be evaporable on sections heated to 50° for 24 hrs and was considered to represent metabolites of HCB. Some radioactivity remained in the liver, the kidney, the heart and the intestinal contents after evaporation and extraction of the sections with polar and nonpolar solvents and was supposed to reflect metabolites of HCB associated to tissue macromolecules. Besides urine and faeces, the results indicated the following excretory pathways: Intestinal mucosa, sebacous glands, nasal mucosa and the praeputial and Harderian gland.
Local Muscle Damage and Oily Vehicles: A Study on Local Reactions in Rabbits after Intramuscular Injection of Neuroleptic Drugs in Aqueous or Oily Vehicles
Authors: Svendsen Ove
Published: July 2010

Abstract: The local muscle damaging effect of a series of neuroleptics formulated in water or in oily vehicles (Viscoleo, sesame oil, methyl oleate or squalane) has been investigated after intramuscular injection in rabbits. Each drug preparation (2 ml) was administered intramuscularly in the central part of the longissimus dorsi muscle of four rabbits. The rabbits were killed three days after the injection, and the injection site was examined macroscopically. Areas of necrotic muscle tissue were isolated by dissection and weighed. All preparations in aqueous solution caused local muscle damage (large necrotic area) at the injection site. This effect was almost completely neutralized by the Viscoleo vehicle. The sesame oil, methyl oleate and squalane vehicles also neutralized the local damaging effect, but not to the same extent as that of the Viscoleo vehicle.
Intramuscular Injections and Local Muscle Damage: An Experimental Study of the Effect of Injection Speed
Authors: Svendsen Ove
Published: July 2010

Abstract: Physiological saline (0.9%) was administered intramuscularly into the longissimus dorsi muscle of rabbits (four animals per group) at different injection speeds (1 ml/sec. or 1 ml/10 sec.) and at different dose volumes (2 or 6 ml). The injection sites were examined post mortem 30 minutes after the injection. The same procedure was used for the administration of a solution of 1 % cis(Z)‐clopenthixol, a neuroleptic drug, in 0.9% NaCl at speeds of 2 ml/2 sec., 2 ml/6 sec., 2 ml/20 sec., or 2ml/60 sec. The injection sites of these rabbits were examined post mortem 3 days after the injection. The muscle tissue at the injection sites was examined for macroscopic changes by serial sectioning. If a demarcated area of necrotic tissue was found, the necrotic area was dissected from the surrounding muscle tissue and weighed. Muscle tissue from rabbits receiving an injection of 0.9 % NaCl was prepared for microscopic examination. In almost all rabbits given 0.9 % NaCl the needle track was indicated by slight bleeding. In some of the rabbits which received 2 or 6 ml of 0.9% NaCl over 2 or 6 sec., slight bleeding was also seen in the muscle tissue adjacent to the needle track. Since no further changes were seen, it is concluded that very fast injection of 0.9 % NaCl only causes slight bleeding probably from disruption of the local tissue. The needle track was identified microscopically by haemorrhages and disruption of muscle fibres. Muscle bundles were separated and muscles fibres were eosinophilic or vacuolated. In the rabbits given 1 % cis(Z)‐clopenthixol, a well‐demarcated area of necrotic muscle tissue was found at the injection sites. There was no difference between the mean weights of necrotic tissues from the groups given 2 ml over 2, 20 or 60 sec. (mean weights ±S.E.M., 5.15 ±0.41, 4.67 ±0.03, or 4.59 ±0.15 g, respectively). However, the mean weight of necrotic tissue from animals given 2 ml over 6 sec. (5.69 ± 0.24 g) was significantly higher than that of the mean weights after injections given over 20 or 60 sec. From these findings it is concluded that injection speed is not an important factor for local damaging effect of intramuscular drug preparations. However, very slow injection may reduce the local damage but only slightly.
New Phorbol and Deoxyphorbol Esters: Isolation and Relative Potencies in Inducing Platelet Aggregation and Erythema of Skin
Authors: Edwards Mary C. , Taylor Stephen E. , Williamson Elizabeth M. , Evans Fred J.
Published: July 2010

Abstract: Diester diterpenes based upon phorbol, 4‐deoxyphorbol, 4α‐deoxyphorbol, 4‐deoxy‐5‐hydroxy‐phorbol and 4,20‐dideoxy‐5‐hydroxyphorbol were isolated from the fruit oil of Sapium indicum. Corresponding tri‐ and tetra‐esters were produced by acetylation and mono‐esters by selective hydrolysis. Twenty‐six compounds were tested for production of erythema in vivo and induction of human and rabbit platelet aggregation in vitro. The flatter shape of the AB‐ring trans compounds is necessary for interaction of phorbolesters at their receptor in that the cis analogues were inactive. The tertiary C‐4 hydroxy group of phorbol was not necessary for activity although the 4‐deoxy derivatives were less potent than the 4‐hydroxy diterpenes. A primary hydroxy group at C‐20 was essential for biological activity because the methyl and aldehyde derivtives of this position were inactive. The C‐20 acetates were also inactive on platelets, but they did produce erythema, possibly because of the removal of the ester due to lipase activity in the skin. 5‐hydroxy‐analogues which undergo intramolecular hydrogen bonding had greatly reduced activities in both systems. Membrane stabilisers, phospholipase A2 and calmodulin inhibitors were antagonists for phorbol esters in platelet aggregation tests, whilst cyclo‐oxygenase inhibitors and free radical scavengers had no inhibitory effects. Consequently, one electron withdrawal and free radical formation plays no part in the biological activity of these compounds.
Hepatic Injury in Rats Due to Prolonged Sub‐anaesthetic Halothane Exposure
Authors: Plummer John L. , de la M. Hall Pauline , Cousins Michael J. , Bastin Fern N. , Ilsley Anthony H.
Published: July 2010

Abstract: Fischer 344 rats of both sexes were exposed to halothane (2‐bromo‐2‐chloro‐1,1,1‐trifluoroethane) at a concentration of 50 p.p.m. for twelve weeks. During the course of the experiment, weight gain of both sexes was depressed and serum alanine aminotransferase activities were elevated, compared to control animals. The temporal pattern of alanine aminotransferase elevation differed between the sexes. After 12 weeks of exposure, liver/body weight ratio was increased in both sexes, and pathological changes were observed in their livers. Livers of all halothane‐exposed animals showed focal liver cell necrosis, considerable lobular disarray and occasional mitoses. Many liver cells showed fatty change. None of these changes were observed in any control animals. These results indicate that prolonged exposure to a low concentration of halothane caused mild liver damage with regeneration. This finding may be of significance to humans occupationally exposed to halothane.
TXA2‐Antagonistic Properties of Agents Affecting Prostaglandin Synthesis or the Cyclic Nucleotide System in Human Platelets
Authors: Kangasaho Mauno , Vapaatalo Heikki
Published: July 2010

Abstract: Prostaglandins (PG) E1 and E2 as well as 3‐isobutyl‐1‐methylxanthine, nitroprusside, dibutyryl cyclic AMP and N‐0164 inhibited platelet aggregation induced by the thromboxane (TX) A2‐mimetic prostaglandin endoperoxide analogue U46619. Non‐steroidal anti‐inflammatory agents – acetylsalicylic acid, indomethacin, tolfenamic acid, flumizole, nictindole and proquazone – did not demonstrate any antagonistic actions on U46619‐induced aggregation at concentrations causing inhibition of prostaglandin/thromboxane synthesis‐dependent forms of platelet aggregation. Comparing with the effects of the different test substances on ADP‐or arachidonic acid‐induced platelet aggregation, it can be suggested that PGE1 and PGE2 as well as 3‐isobutyl‐1‐methylxanthine, nitroprusside, and dibutyryl cyclic AMP are functional antagonists and N‐0164 is a receptor level antagonist of TXA2 in platelets.
The LD50 test and in vitro toxicology strategies.
Authors: Nardone R. M.
Published: July 2010

Abstract In order for in vitro alternatives for acute toxicity testing to emerge, it will be necessary to stage a clearly‐defined strategy. The strategy, with its intermediate objectives and proximal decision points, could serve as the basis for validation of the in vitro tests to be used as components of a test battery for assessment of general cytotoxicity and for the evaluation of impairment of differentiated function. An approach for the evaluation of potential neurotoxic agents is presented and could serve as a model for the evaluation of potential ocular, hepatic, and other toxins.
Potentiation of Hepatotoxicity by Ethanol in Galactosamine‐induced Hepatitis in Rats: Role of Propylthiouracil Protection
Authors: Nadkarni G. D. , Naik Suvita B. , Talavdekar R. V. , Soman Chitralekha S. , Talwalkar G. V. , Ganatra R. D.
Published: July 2010

Abstract: Chronic ingestion of ethanol (5 g/kg/day)for 6 weeks increased the hepatotoxicity of a single injection of D‐galactosamine (330 mg/kg) in rats. Plasma transaminases, alkaline phosphatase, gamma glutamyl transpeptidase and sulphobromophthalein retention were consistently high in alcohol‐fed rats compared to sucrose‐fed controls, 25 hours after galactosamine administraction. Liver histology in sucrose‐fed rats revealed typical inflammatory changes and cytoplasmic vacuolation without cell necrosis was seen. Propylthiouracil treatment had no beneficial or protective effect in alcohol‐fed rats in this animal model of hepatitis.
The Antinociceptive Effect of Ketobemidone in Comparison with Ketogin®
Authors: Larsen J.‐J. , Christensen A. V.
Published: July 2010

Abstract: The antinociceptive effect of ketobemidone, A 29 (N,N‐dimethyl‐3,3‐diphenyl‐l‐methyl‐alkylamine chloride) and Ketogin (combination of ketobemidone and A 29) has been investigated in mice and rats. The hot plate, grid shock, phenylquinone and Randall‐Selitto test were used. Ketobemidone caused antinociception whereas A 29 was without effect. Ketogin was in comparison with ketobemidone more potent. The mechanism of the potentiating effect of A 29 remains to be clarified.
The Ulcerogenic Effect on the Oesophagus of Three β‐Adrenoceptor Antagonists, Investigated in a New Porcine Oesophagus Test Model
Authors: Olovson Stig‐Göran , Björkman Jan‐Arne , Ek Lars , Havu Niilo
Published: July 2010

Abstract: Drug‐induced oesophageal lesions have attracted increasing attention during the past few years. A test model is presented for assessing irritative or ulcerogenic effects of potential drugs on the oesophagus. In this model the pig oesophagus is used, as it is more similar to the human oesophagus than models used in other techniques that have been suggested. The β‐blockers, alprenolol and propranolol, displayed the same ulcerogenic properties with this test model as reported with other test models in the literature. The β1‐selective blocker metoprolol, did not have such ulcerogenic effects. The pig model is suggested as the method of choice in evaluating the potential irritative or ulcerogenic effects of pharmaceutical formulations intended for human use.