bluuebunny/crossref_metadata_2025 huggingface dataset:
Vascular Anti‐permeability Effects of β‐receptor Agonists and Theophylline in the Lung
Authors: Persson C. G. A. , Ekman M. , Erjefiält I.
Published: July 2010

Abstract In conscious guinea‐pigs the effect of theophylline, terbutaline and isoprenaline on histamine‐induced increase in lung weight was examined. Animals exposed to a saline aerosol had a lung weight to body weight ratio of about 0.8 %. Exposure to a histamine aerosol raised this value to about 1.1(P <0.001). Theophylline 55 mg/kg and 110 mg/kg was given orally, terbutaline 0.1 mg/kg and isoprenaline 0.01 mg/kg and 0.03 mg/kg subcutaneously before exposure to histamine. The three drugs prevented the lung weight effect produced by histamine aerosol (P<0.01, P<0.001, P<0.001, P<0.1, P<0.001 respectively). Changes in lung blood content did not contribute to the weight‐reducing effects. The potency ratio found between terbutaline and isoprenaline suggests that β‐2‐receptors might be involved in the anti‐permeability effect. Propranolol‐treated animals did not survive in the histamine‐aerosol unless they received theophylline; neither bronchodilator nor anti‐permeability effects of theophylline were antagonized by propranolol. It is concluded that in guinea‐pigs theophylline and β‐agonists, in bronchodilating doses have the additional effect of preventing permeability oedema in the lung.
Studies on the Handling of Retinotoxic Doses of Iodate in Rabbits
Authors: Olsen K. J. , Ehlers N. , Schønheyder F.
Published: July 2010

Abstract Accumulation of iodate in eye tissues and fluids as a possible explanation of the retinotoxic effect of iodate has been studied by intravenous injection of NaIO3(30 mg/kg), 125IO‐3 and 131I‐ in rabbits. 125IO‐3 was determined in fluids and tissue extracts by precipitation with BaCl2 after addition of KIO3. 125IO‐3 was rapidly broken down in blood T1/2 = 14 min.). 125IO‐3 was not present in aqueous humour, vitreous or extracts from retina, choroid + pigmentary epithelium or liver. Concentrations of 125I were comparable in blood, choroid + pigmentary epithelium and liver tissue while in vitreous and aqueous humour low concentrations of 125I were found which, however, increased gradually during 5 hrs after injection to reach levels comparable with blood levels of 125I. Retina had a low concentration of 125I. The ratio 125I/131 I (R) in blood decreases during the first 60 min. after injection followed by a slow rise. R in retina, choroid + pigmentary epithelium and liver was the same as in blood at the same time after injection. During the first 80 min. after injection R was higher in vitreous than in blood while it was lower in aqueous humour than in blood. At longer times after injection R was identical in the three fluids, The investigation has been supplemented with whole body scintigraphy of rabbits injected with NaIO3 (30 mg/kg) and 131IO‐3 or 131I‐. The reduction kinetics of IO‐3 to I‐ by some body fluids, tissues, cystein and glutathione was also studied. It is concluded that the retinotoxic effect of iodate is not due to accumulation of IO‐3 in eye tissues, but more likely to damage to biochemical mechanisms involved in the reduction of IO‐3 to.
Ornithine Decarboxylase Activity and Polyamine Content of Normal and Fluoride Resistant LS Cells
Authors: Hongslo Jan K.
Published: July 2010

Abstract The activity of ornithine decarboxylase (ODC) in suspension cultures of mouse fibroblasts. LS cells, varied in a characteristic cyclic pattern after dilution of the cultures. Two strains of fluoride resistant LS cells, FR6 and LSFR6 cells, exhibited the same cyclic pattern, but with markedly higher ODC activities. These fluoride resistant cells, however, contained less putrescine, the product of the ODC reaction. Possible reasons for this finding are discussed.
Ascitic Fluid Modifying the Distribution of Sulphafurazole in Rats with Intestinal Occlusion
Authors: Venho V. M. K. , Mattila M. J.
Published: July 2010

Abstract In order to confirm our previous findings of increased sulphafurazole (sulfisoxazole, SF) inactivation by intestinal occlusion, SF was given intravenously 20 mg/kg to rats with a low small intestinal occlusion and to sham‐operated controls 40‐45 hours after the operation. Occlusion did not cause major changes in the distribution of SF to various tissues, but there were some indications of increased SF acetylation after occlusion. The occlusion rats produced ascitic fluid into the abdominal cavity and the total SF levels in the ascitic fluid were almost identical to those in blood, also after oral administration of SF, 50 mg/kg. After intraperitoneal administration of 2 ml of SF (60 μg/ml) more SF accumulated into the small intestinal wall in occlusion rats than in controls, and the acetyl SF levels were increased in the small and large intestine. So, our previous suggestion of an increased excretory function of the large intestine in occlusion states may not be the only explanation for increased drug levels in the large intestine found after oral administration of SF. Part of the SF in the intestinal wall can also result from ascitic fluid SF, and ascites must be taken into account when considering drug pharmakokinetics.
Sotalol Intoxication, Two Patients with Concentration ‐ Effect Relationships
Authors: Neuvonen Pertti J. , Elonen Erkki , Tarssanen Leo
Published: July 2010

Abstract Two adult patients ingested an overdose of 2.4 g and 8.0 g of sotalol hydrochloride, respectively, i.e. 7‐25 times the mean daily dose. Certain signs as bradycardia and hypotension were similar to those described for other beta‐blocking agents. In addition to these, however, both patients had severe cardiac tachyarrhythmias and a considerably prolonged QT‐interval in their electrocardiogram. The decline of serum sotalol concentrations followed first‐order kinetics with the elimination half‐life of 13‐15 hours. There was a good correlation between the serum sotalol concentration and the prolongation of the QT‐interval. Sotalol differs from other beta‐blocking agents in its effects on the action potential of the ventricular muscle and Purkinje fibers of the heart. This is likely to explain the different symptoms and findings of sotalol intoxication compared to those seen in connection with other beta‐blocking agents.
Absorption of Diazepam in Man Following Rectal and Parenteral Administration
Authors: Magnussen I. , Oxlund H. R. W. , Alsbirk K. E. , Arnold E.
Published: July 2010

Abstract Serum concentrations of diazepam and N‐desmethyldiazepam were measured in six adult patients following administration of 10 mg diazepam in solution by the rectal, intravenous, and intramuscular routes. Maximum serum concentrations of 121‐200 ng/ml were recorded from 10 to 20 min. after the rectal instillation, whereas following intramuscular injection the levels rose slowly and irregularly, reaching a maximum (62‐186 ng/ml) in 1 to 24 hours. The bioavailability of diazepam given by rectal instillation was found to be 50±17 per cent (mean±S. D.) as compared with the intravenous administration. The possible reasons for the low bioavailability are discussed. It is concluded that administration by rectal tube provides a useful alternative to the tablets (and intramuscular injections) when a rapid onset of effect of the drug is wanted, and when intravenous administration is not applicable or practical.
Pharmacological Modification of Experimental Tardive Dyskinesia
Authors: Báráy Sven , Gunne Lars ‐M.
Published: July 2010

Abstract Cebus apella monkeys subjected to chronic haloperidol administration develop neurologic disturbances very similar to neuroleptic‐induced acute dystonia in human beings. After varying lengths of time, certain monkeys develop a prolonged dyskinetic syndrome resembling tardive dyskinesia (TD), as seen clinically. Two monkeys with signs of TD were given single intramuscular injections of various compounds with known effects on the catecholaminergic, cholinergic, serotoninergic and GABA‐ergic neurotransmittor systems, and their effect on the TD signs were rated. Dopamine receptor blockers as well as cholinergics had an ameliorating effect on the symptoms. Some compounds known to activate the GABA system, including some benzodiazepines and the GABA‐transaminase inhibitor amino‐oxyacetic acid, also reduced the symptoms, as did the serotonin precursor L‐5HTP. Results with serotonin antagonists were equivocal. It is concluded that dopamine receptor blockade, as well as increased activity within the GABA‐ergic or cholinergic systems cause alleviation of TD. The findings are in agreement with earlier reports in man and thus seem to validate this primate model.
Inhibition of Apomorphine‐Induced Climbing in Mice by Cholinergic Drugs and Neuroleptics
Authors: Lassen J. Buus
Published: July 2010

Abstract Apomorphine (ap) was administered subcutaneously to mice kept in individual cages. Ap elicited an abnormal vertical climbing behaviour. The muscarinomimetics physostigmine and oxotremorine as well as the neuroleptics clozapine and haloperidol inhibited the climbing produced by ap 1 mg/kg. A small inactive dose of physostigmine potentiated the effect of clozapine but not that of haloperidol. The anticholinergic atropine antagonized the effect of physostigmine, oxotremozine, clozapine and haloperidol. The climbing behaviour produced by ap is presumably due to stimulation of dopamine receptors and this effect can be antagonized either by blockade of dopamine receptors or by activation of muscarinic receptors. Some lines of evidence suggest that the ap‐inhibitory effect of clozapine may be partly due to a muscarinomimetic effect.
Central Cardiovascular Effects of Gamma‐Hydroxybutyric Acid: Interactions with Noradrenaline, Serotonin, Dopamine and Acetylcholine Transmission
Authors: Persson B. , Henning M.
Published: July 2010

Abstract:Gamma‐hydroxybutyric acid (GHBA) increased arterial blood pressure and heart rate dosedependently following intraperitoneal and intracerebroventricular administration to conscious rats. Cardiovascular responses to GHBA were completely prevented after pretreatment with reserpine or phenoxybenzamine and after a prehypothalamic brain transection. Intraperitoneal GHBA increased brain noradrenaline (NA) synthesis and utilization, particularly in the neocortex. Selective central NA depletion in combination with NA synthesis inhibition prevented the cardiovascular effects of GHBA. No overt interactions were observed with agents influencing 5‐hydroxytryptamine (5‐HT), dopamine (DA), or acetylcholine (Ach) transmission. Pentobarbitone but not diazepam or diphenylhydantoin abolished the hypertensive properties of GHBA. We conclude that the cardiovascular effects of GHBA are of central origin and that they are mediated via the peripheral sympathetic nervous system. They are dependent on an intact central NA transmission while there are few indications for a significant role of central DA‐, 5‐HT or Ach‐mechanisms.
Dextran‐Induced Anaphylactoid Reaction in Man: Altered Reactivity of High Molecular Weight Kininogen
Authors: Briseid Gudrun , Briseid Kjell
Published: July 2010

Abstract: Normal levels of factor XII and of high and low molecular weight kininogens (HMWK and LMWK) were registered in plasma specimens from 5 individuals who had developed anaphylactoid reactions upon injection of dextran during surgery (dextran reactors, DR). Factor XII was assayed as prekallikrein activator (PKA) activated with kaolin at 0°. and kininogen fractions were estimated through the release of kinin caused by plasma kallikrein or hog pancreas kallikrein (HPK). Subnormal levels of factor XII apparently present in plasma from one DR, and after affinity chromatography on a lysine‐Sepharose column also in plasma from another DR, were normalized by addition of plasma deficient in factor XII or by addition of purified HMWK. Treatment of plasma from DR with acetone (25% v/v) induced a conversion of HMWK into a state which was non‐functional as a cofactor in the surface‐dependent activation of factor XII, and the passage of plasma from DR through a lysine‐Sepharose column altered the HMWK present to a substance that released kinin only very slowly by incubation with HPK. It is concluded that the treatments mentioned will favour the activation in plasma from DR of a factor that will cause the conversion of HMWK. Previous experiments with rat plasma demonstrated that plasmin and also a plasmin‐like factor without affinity for lysine‐Sepharose were able to destroy the capacity of HMWK to function as a cofactor in the surface‐dependent activation of factor XII, without a corresponding release of kinin.
The Binding of Thiopental to Serum Proteins Determined by Ultrafiltration and Equilibrium Dialysis
Authors: Christensen Jargen Heslop , Andreasen Frederik , Jensen Eva Bjørn
Published: July 2010

Abstract: An ultra filtration method is described by which it is possible to estimate the protein bound fraction of a drug at its original concentration in a serum sample. The determination is carried out at 37° and pH 7.4. For thiopental no difference was found between the values of protein binding whether they were determined by the ultrafiltration method or by a less time consuming equilibrium dialysis against an equal volume of phosphate buffered isotonic sodium chloride solution. The equilibrium dialysis was used to measure the concentration of bound and unbound thiopental molecules; and the binding parameters in a two class binding model were determined. No evidence was found for binding to other proteins than albumin. About one binding site belonging to the first class was found per 1000 albumin molecules whereas an average of about 5 secondary sites were found for each albumin molecule. The association constants for the primary class of binding sites were 3.4×106M−1 for albumin and 13.3×106M−1 for serum while the values for the secondary class were 2.2 and 1.2×103M−1 for albumin and serum respectively. The estimates of association constants and number of binding sites were based on experiments with total thiopental concentrations ranging from 0.4 to 80 μg/ml. In a phosphate buffered albumin solution with 2 g albumin per 100 ml, a pH increase from 5 to 8 caused an increase in protein binding from 36 to 76%. A Scatchard plot using data from experiments with increasing albumin concentrations resulted in a “plot” with positive slope. The use of a curve like this is discussed and it is concluded that the binding parameters for thiopental are influenced by the albumin concentration.
The Effect of Metal Salts on the Distribution of Iron‐59 in Rats: Manganese (II), Nickel (II) and Tin (II)
Authors: Dwivedi R. S. , Kaur G. , Jaiswal R. K. , Srivastava* R. C.
Published: July 2010

Abstract: The disappearance and reappearance of iron‐59 in plasma and blood at various time intervals has been studied in control, manganese, nickel and tin administered and anaemic rats after a single intravenous injection of an aqueous solution of radioactive iron (III) citrate. Significant difference was observed in the rate of reappearance of iron‐59 in the circulation between control and manganese treated animals. The disappearance of iron‐59 from the plasma of control and treated animals however did not show any appreciable difference. A significant increase in the radio‐iron content was observed in bone marrow, liver and kidney of treated animals as compared to control group forty eight hours after Fe‐59.
Effects of Ethanol on Human Lymphocyte Levels of Cyclic AMP In Vitro: Potentiation of the Response to Isoproterenol, Prostaglandin E2 or Adenosine Stimulation
Authors: Hynie Sixtus , Lanefelt Fred , Fredholm Bertil B.
Published: July 2010

Abstract: The effects of ethanol, acetone and dimethylsulfoxide (DMSO) were tested on the accumulation of cyclic AMP in human peripheral blood lymphocytes in vitro. Isoproterenol (1.0×10−8 ‐ 1.0×10−4M), PGE2 (3×10−8 ‐ 3×10−6M), adenosine (10−7 ‐ 10−4M) and phenylisopropyladenosine (10−8 ‐ 10−4M) caused a dose dependent increase in cyclic AMP accumulation. Over the entire range of concentration of stimulating drugs, ethanol caused an enhanced accumulation of cyclic AMP. At temperatures between 15° and 30° the effect of ethanol rose with increasing concentration from 0.2–6%. At 37° and 40°, 6% ethanol had less stimulatory effect than 2% ethanol. The effect of ethanol was shared by acetone and to a minor extent by DMSO, and was present also when phosphodiesterase was inhibited by isobutylmethylxanthine. It is suggested that ethanol enhances adenylate cyclase activity as a consequence of altered cell membrane fluidity. Since the effects on cyclic AMP accumulation can be observed already at rather low concentration of the solvents they may be of toxicological significance.
Studies on the Interaction and Distribution of Selenite, Mercuric, Methoxyethyl Mercuric and Methyl Mercuric Chloride in Rats. II. Analysis of the Soluble Proteins and the Precipitates of Liver and Kidney Homogenates
Authors: Mengel Helle , Karlog Ole
Published: July 2010

Abstract In a 5 weeks' study rats were given mercuric, methoxyethyl mercury and methyl mercury alone or together with sodium selenite. The distribution of mercury and selenium among the soluble proteins of liver and kidneys has been investigated by gel chromatography. Estimates of the ratios of the concentration of mercury (selenium) of the soluble proteins to that of the precipitates of liver and kidney homogenates are reported. The ratios seem to decrease when selenium is given concomitant with mercury. When mercuric chloride was given alone, 50 per cent of the mercury content in the soluble kidney proteins was found in the fractions of proteins with a molecular weight similar to that of metallothionein. No mercury could be detected in these fractions when both mercuric chloride and sodium selenite were given.
Small Animal Inhalation Chambers and the Significance of Dust Ingestion from the Contaminated Coat when Exposing Rats to Zinc Chromate
Authors: Langård Sverre , Nordhagen Anne‐Lise
Published: July 2010

Abstract The relative significance of dust ingestion during and after short‐term inhalation exposure to a zinc chromate aerosol has been studied. Two groups of rats were exposed in the same dust cloud, one in open wire cages and the other in fiber glass tubes. The chromium excretion during the following 21/2 days was 8.4 times higher in faeces and 5.5 times higher in urine in the animals exposed in cages, compared with those exposed in tubes.
Tissue Distribution of 14C‐Lynestrenol in Pregnant Rats
Authors: Sannes E. , Nafstad I.
Published: July 2010

Abstract The tissue distribution of 4‐14C‐lynestrenol (17 α‐ethynyl‐oestr‐4‐en‐17β‐ol) following oral administration to pregnant rats was studied by whole body autoradiography and liquid scintillation counting. Pregnant females were sacrificed on days 10, 12, 14 and 19 of gestation, in each case 5 hours after oral administration of 43 μCi 4‐14C‐lynestrenol per animal. The isotopelabelled compound was distributed throughout most tissues, including the fetuses. The highest concentrations were found in the liver, while there was lower activity in the fatty tissues and the activity in the fetuses was comparable with that in the brain. The placental transfer was verified by the results of liquid scintillation counting. The concentration of labelled substance in the fetuses increased with the duration of pregnancy.
Skin Carcinogenesis as a Model System: Observations on Species, Strain and Tissue Sensitivity to 7,12‐Dimethylbenz(a)anthracene with or without Promotion from Croton Oil
Authors: Stenbäck Frej
Published: July 2010

Abstract The pattern of development of tumours was studied in several mice strains, rabbits and pigs. Repeated carcinogen applications caused the appearance of numerous papillomas, keratoacanthomas and squamous cell carcinomas in Swiss, A, ASW/SN, Balb/c and C57B1 mice, New Zealand and outbred laboratory rabbits. AKR mice were only little sensitive and Hormel mini pigs unresponsive. Initiation with 7,12‐dimethylbenz (a) — anthracene and promotion with croton oil produced in Swiss, A, Balb/c and C3H mice as well as New Zealand rabbits a large number of squamous papillomas. Pigmented or adnexal tumours were not observed, and only a few dermal fibromas and fibrosarcomas.
Bioavailability and Pharmacokinetics in Man of Orally Administered Theophylline
Authors: Nielsen‐Kudsk F. , Magnussen I. , Jensen T. Staehelin , Næser K.
Published: July 2010

Abstract The pharmacokinetics of theophylline after both intravenous and oral administration was investigated in six hospitalized patients with normal renal, hepatic and pulmonary functions. A rather wide range of biological half‐lives from about 3–16 hours and plasma clearance values of about 16.5–115 ml kg‐1 hr‐1 were found in the investigated patients, who were from 31 to 73 years of age. The apparent volumes of distribution during the eliminatory β‐phase (Vdβ) were within the range 0.394–0.616 1 kg‐1 with a mean value of 0.484 1 kg‐1 ±0.082 S.D., as determined from the intravenous data, and in excellent agreement with the value obtained from the peroral data. Except in one case theophylline exhibited two compartment characteristics after intravenous administration, while the oral data in only one patient showed this pharmacokinetic configuration and had to be analysed according to one‐compartment characteristics in the other five subjects. In the oral experiments absorption rate constants of from about 0.57 to 2.17 hr‐1 were found for the administered microparticulate theohylline tablet preparation, Nuelin® from Riker Laboratories. A wide range of lag‐times from 0 to 1.32 hours were also demonstrated in the experiments. The systemic availability of theophylline in this preparation varied from 82.8 to 103% as determined on basis of the ratios of areas under the oral and intravenous serum concentration curves. It is conclusively stated that therapeutic plasma concentrations of theophylline probably may be maintained and controlled efficiently with the investigated oral theophylline preparation. Because of the interindividual variability in the biological half‐life of the compound monitoring of the serum theophylline concentration is generally advised in order to avoid toxic side effects, in particular in relation to the initial establishment of a therapeutic serum concentration level in the individual subjects to be treated.
Plasma HDL Cholesterol and Growth Hormone in Epileptics Treated with Anticonvulsants
Authors: Luoma P. V. , Myllyla V. V. , Sotaniemi E. A. , Hokkanen T. E. J.
Published: July 2010

Abstract: Plasma high density lipoprotein (HDL) cholesterol and serum growth hormone (GH) levels were determined in 166 epileptic patients undergoing anticonvulsant treatment and in 54 healthy controls. HDL cholesterol and GH levels were high in epileptics when compared to the levels in controls. Nineteen out of 31 patients (61%) with elevated GH had elevated plasma HDL cholesterol concentration. This relationship in patients with normal GH was 34/135 (25 %). In female epileptics with elevated GH plasma HDL cholesterol was in positive relationship to serum GH level (r = 0.47, P<0.05). The increase in GH secretion in epileptics might be associated with an increase in hepatic production of HDL.
Effects of Different Monoamine Oxidase Inhibitors on Respiratory Activity in Rats with Chronically Impaired Central Serotonergic Function
Authors: Mueller R. A. , Lundberg D. , Breese G.
Published: July 2010

Abstract:Resting and CO2stimulated respiration were measured by means of a whole‐body plethysmograph in rats lightly anaesthetized with halothane. Rats pretreated neonatally with intracisternal 5,7‐dihydroxytryptamine (5,7‐DHT) to destruct permanently central serotonergic neurones had significantly lower resting and CO2stimulated respiratory frequency (RF) and minute volume (VM) than naive rats. In the 5,7‐DHT pretreated rats, but not in naive rats, the monoamine oxidase inhibitors clorgyline and pargyline further reduced both resting and CO2stimulated RF and Vm, whereas 1‐deprenyl stimulated respiration. The results provide additional evidence that monoaminergic mechanisms are involved in central modulation of respiration in which activation of a serotonergic neuronal system depresses, and dopaminergic activation stimulates respiration.
Haemorrhagic Toxicosis in Rats Given Butylated Hydroxytoluene
Authors: Takahashi Osamu , Hiraga Kogo
Published: July 2010

Abstract: Vascular permeability, platelet function, blood coagulation and fibrinolytic activity were examined in Sprague‐Dawley male rats given 1.20% butylated hydroxytoluene (BHT) in the diet for 1 week. BHT significantly increased the leakage of Evans blue from blood into epididymus. BHT inhibited the ADP‐induced platelet aggregation and decreased the platelet factor 3 availability. Plasma prothrombin, factors IX, X, VII and VIII were decreased in rats given BHT. Fibrinolytic activity was little influenced by BHT‐feeding.
Distribution and Biotransformation of Methyl Mercuric Chloride in Different Tissues of Mice
Authors: Mehra M. , Choi B. H.
Published: July 2010

Abstract: The distribution of 203Hg radioactivity has been studied in various organs of adult male and female mice from one hour to 21 days after treating with 203Hg‐labeled methyl mercuric chloride (MMC). The amount of methyl mercury (MeHg) and inorganic mercury (Hg) has also been determined by injecting single doses of non‐radioactive MMC, and subsequently measuring total, organic and inorganic Hg content by atomic absorption technique. In addition, photoemulsion histochemical method (PEHM) was used to demonstrate localization of Hg grains in various cellular compartments of organs and tissues. The highest levels of radioactivity were attained at 7 hours post‐treatment in all organs except for brain and testis. The testis showed the highest radioactivity at one day and the brain at two days post‐treatment. MeHg persisted in brain over a longer period though the level was not as high. The content of MeHg and inorganic Hg was maximum in kidneys as compared to other organs. The brain and the reproductive organs contained the least amount of inorganic Hg. By PEHM, Hg grains were most prominently observed in the sinusoids, Kupfer cells, hepatic cells and bile duct epithelium of liver; in the lumen of blood vessels, convoluted and collecting tubules of kidneys; and in the gastrointestinal epithelium. The pattern of uptake and distribution of MeHg correlated well with the morphological demonstration of Hg grains in tissue sections.
Pharmacokinetics of Diazepam Administered Rectally in Geriatric Patients: Comparison of Suppositories with Rectal Tubes in a Cross‐over Study
Authors: Viukari M. , Salo H. , Lamminsivu Ulla , Auvinen R. , Gordin A.
Published: July 2010

Abstract: The pharmacokinetics of diazepam administered as suppositories or as a solution in rectal tubes were compared in six geriatric hospital patients. A single dose of 10 mg was administered in a cross‐over study with a one week interval. There was no statistically significant difference in the bioavailability, the mean maximum serum concentration or the time of achievement of the maximum with these preparations. However, the peak concentration was somewhat higher with suppositories but the absorption was somewhat faster via rectal tubes. The serum N‐desmethyldiazepam concentration increased during the whole 24 hour observation period, and there was no difference between the preparations. Our results are in good agreement with most studies of the pharmacokinetics of diazepam. The basal substance of the suppository is of the utmost importance to the absorption of diazepam. The rectal tube for administration of diazepam did not have any advantage over the optimally formulated (a mixture of macrogols) suppository in geriatric patients. In fact, the use of rectal tubes is more expensive, the tube may not be completely emptied, and the solution may not be completely retained in the rectum.
Incorporation of Thiouracil and some Related Compounds into Growing Melanin
Authors: Dencker L. , Larsson B. , Olander K. , Ullberg S. , Yokota M.
Published: July 2010

Abstract: Several drugs, mainly polycyclic amines, are accumulated in melanin‐containing tissues. They are bound to preformed melanin (both in vivo and in vitro). Thiouracil is accumulated into melanin according to another principle: It is incorporated as a false precursor during melanin formation. It is thus taken up only in growing melanin, e.g. in the eye of pigmented mouse foetuses or in melanomas. The acceptance of a foreign substance during the formation of a foetal tissue seems theoretically important. We are also interested in the practical viewpoint of using false melanin precursors as selective melanoma seekers. Some related substances are therefore compared with respect to incorporation into growing melanin. The thiouracil uptake in the ocular melanin of a 5 day old mouse was 276 times higher than that of a 3 month old mouse based on weight units of melanin. Thiourea is incorporated in growing melanin as well but also binds slightly to preformed melanin. Uracil and fluorouracil showed no specific uptake into growing melanin. It thus seems as if the sulfur is essential for the incorporation into the melanin polymer. 35S‐thiouracil and 2‐thio(2‐14C)uracil showed the same high uptake, indicating that at least part of the uracil moiety is incorporated together with the sulfur. There seems to be a relation between the property to be incorporated into melanin and the thyrostatic activity. Both in the formation of melanin and thyroid hormones, tyrosine is the physiological precursor and both reactions are catalyzed by oxidizing enzymes. Properly labelled thiouracil derivatives seem to be promising melanoma seekers for diagnostic and radiotherapeutic purposes.
Effects of Lithium and Neuroleptics and Combinations of the Two on Renal Function and Structure in Rats
Authors: Christensen Sten , Kristensen Anne Riise , Faarup Poul
Published: July 2010

Abstract: The effects of 8 weeks of treatment with lithium and neuroleptics, alone and combined, on renal concentrating ability and morphology were studied in rats. LiCl was administered in the diet and neuroleptics were given as one daily dose: haloperidol 1 mg/kg, chlorpromazine 15 mg/kg, and perphenazine 4 mg/kg. Plasma lithium levels were about 1 mmol/l, and the area under the plasma concentration curve was not statistically different in the control and neuroleptic groups. Rats treated with lithium developed marked polyuria which was less in rats receiving neuroleptics concomitantly. After 8 weeks, rats treated with lithium alone showed marked impairment of renal concentrating ability and moderate degree of structural renal changes. Neuroleptics alone had no effect on concentrating ability or renal morphology, nor did they aggravate the changes caused by lithium. In fact, neuroleptics seemed to improve the concentrating ability in rats treated with lithium. It is concluded that in rats high doses of neuroleptics do not potentiate lithium‐induced functional and structural renal changes.
Effect of Aldrin on Carbohydrate Metabolism in Indian Catfish*
Authors: Srivastava Anil K. , Singh Narendra N.
Published: July 2010

Abstract:Exposure of the Indian catfish (Heteropneustes fossilis) to a sublethal concentration of 0.14 p.p.m. aldrin for 3, 6, 12, 48, and 96 hrs affected carbohydrate metabolism. Muscle glycogenolysis and glycogenesis were obtained at 3 and 12 hrs, respectively. Hepatic glycogenolysis occurred at 3, 48, and 96 hrs. The treatment caused hyperglycaemia at 3, 6, 48, and 96 hrs, and hypoglycaemia at 12 hrs. Blood pyruvate values increased significantly at 3, 6, and 96 hrs. Hyperlacticaemia was observed at 3 and 12 hrs but hypolacticaemia developed at 96 hrs. The results are discussed in relation to acute stress syndrome. Also, impairment of carbohydrate metabolism by aldrin may be involved in the biochemical mechanism for its toxic action. It is concluded that evaluation of carbohydrate metabolites in fish could prove useful as a rapid method for assessing acute toxicity of pesticides.
Methodological Aspects of Studies on the 5‐HT Uptake Mechanism in Normal Platelets
Authors: Malmgren Rigmor
Published: July 2010

Abstract:The 5‐HT uptake mechanism in human platelets was studied in undiluted and diluted platelet‐rich plasma (PRP). The kinetic data obtained, which were based on 5‐HT concentrations ranging from 0.17 to 1.7 μmol/1, were analyzed according to Lineweaver‐Burk, Eadie‐Hofstee, Scatchard and Sips. In undiluted PRP all the analyses revealed a strict linearity between 5‐HT concentrations and initial uptake velocities. Only one site for active transport seemed to be involved and no passive diffusion was present. The apparent Kmand Vmaxin a 95 per cent confidence interval (n = 25) were 1.20 ± 0.14 μmol/1 and 1.40 ± 0.15 pmol/106platelets and minutes, respectively. Dilution of PRP with autologous platelet‐poor plasma or Ringer's solution markedly influenced the active 5‐HT transport mechanism. The addition of minute amounts of supernatant from lysed autologous platelets to PRP totally impaired the active 5‐HT uptake. It is concluded that relevant studies on the active 5‐HT transport can be performed only in fresh undiluted PRP. The commonly used Lineweaver‐Burk analysis does not discriminate sufficiently between fully saturable and non‐saturable transport mechanism and therefore cannot be used for the detection of irregularities in the 5‐HT transport.
Distribution of Intratracheally Administered Cadmium in Rats
Authors: Tandon S. K. , Asokan P.
Published: July 2010

Abstract: Cadmium chloride cleared rapidly from the lungs and translocated mainly into the liver within 24 hrs of an intratracheal instillation. Further pulmonary clearance and hepatic accumulation were very slow during the remaining observation period of 24 days. Though, the uptake of cadmium by kidneys was lower but the level increased consistently with the time after instillation. The induction of metallothionein synthesis by cadmium might be responsible for accumulation and retention of cadmium in liver and kidneys significantly.
Sulfonamide Acetylation in Isolated Rabbit and Rat Liver Cells
Authors: Olsen Harald , Mørland Jørg , Rothschild Marcus A.
Published: July 2010

Abstract:Suspensions of isolated liver cells were prepared from rabbit livers perfused with Ca++‐free buffer and 0.05% collagenase. Primary cell suspensions (containing both parenchymal and non‐parenchymal liver cells) metabolized sulfadimidine and sulfanilamide at first‐order kinetics for at least 2–3 hrs. Suspensions of purified rabbit liver parenchymal cells had an equal metabolic capacity, and it could be demonstrated that the metabolic rate of both sufadimidine and sulfanilamide was correlated to the amount of viable parenchymal cells in suspension. Suspensions of non‐parenchymal cells were lacking the ability to metabolize both drugs. By means of homogenates of purified rabbit and rat liver cells, it could be demonstrated that the enzyme N‐acetyltransferase was located in the cytosolic fraction of the parenchymal cells. It was concluded that the cytosolic fraction of the liver parenchymal cells is the main site of sulfonamide acetylation in both rabbit and rat.
Effects of Acute Exposure to Methyl Parathion on Carbohydrate Metabolism of Indian Catfish (Heteropneustes fossilis)
Authors: Srivastava Anil K. , Singh Narendra N.
Published: July 2010

Abstract: Exposure of the Indian catfish (Heteropneustes fossilis) to a high sublethal concentration of 5.6 p.p.m. (0.8 of the 96 hr LC50) of methyl parathion for 3,6,12,48, and 96 hrs affected carbohydrate metabolism. Muscle glycogen levels decreased significantly at 3,6,12 and 96 hrs; liver glycogen content declined at 6 hrs but there was a resynthesis of hepatic glycogen stores at 12 hrs. Blood glucose levels in fish were elevated at 3 and 6 hrs. Mean values for blood pyruvate were elevated significantly at 6,12, and 96 hrs. Blood lactate level was elevated at 3 hrs but hypolactaemia resulted at 48 and 96 hrs in pesticide‐treated fish. The observed effects of methyl parathion on carbohydrate metabolism in fish are discussed in relation to acute stress syndrome. Measurement of carbohydrate metabolites in fish for 3 hrs or longer could prove useful as a rapid method for evaluating toxicity of pesticides and other toxicants.
Mercury, Arsenic, Cadmium, Selenium and Zinc in Human Hair and Salmon Fries in Iceland
Authors: Jóhannesson Torkell , Lunde Gulbrand , Steinnes Eiliv
Published: July 2010

Abstract: Hair samples were taken from 58 persons living in five localities in Iceland as well as inside as outside areas with known volcanic and geothermal activities. Hg, As, Cd, Se and Zn were determined in the samples by neutron activation analysis. The As levels were uniformly low and the Hg levels were considered as rather low. The levels of Cd, Se and Zn were characterized as normal. For comparison Hg, Cd, Se and Zn were determined in salmon fries from four rivers, some of which have been affected by volcanic or geothermal activity. Hg levels in the fries were within normal limits and Zn levels were the same in the hair and salmon fries. The results indicated that salmon might accumulate Cd and especially Se. Volcanic and geothermal activity do not appear to increase the body burden of Hg in the Icelandic population.
Effect of Heavy Metals on Dopamine, Noradrenaline and Serotonin Uptake and Release in Rat Brain Synaptosomes
Authors: Komulainen Hannu , Tuomisto Jouko
Published: July 2010

Abstract: The effects of some heavy metals on the initial high affinity uptake and spontaneous release of tritiated dopamine (3H‐DA), noradrenaline (3H‐NA) and 5‐hydroxytryptamine (3H‐5‐HT) were studied in vitro in rat striatal, cortical and hypothalamic synaptosomes, respectively. As uptake inhibitors, metals were quite inactive in these conditions. At 10 μM Cu2+ was most potent, inhibiting 3H‐DA and 3H‐5‐HT uptake nearly completely while inhibition of 3H‐NA uptake varied. 3H‐DA uptake was in addition inhibited slightly by Zn2+, sometimes by Sn2+ but never by Co2+, Hg2+ or Mn2+. Unexpectedly Pb2+ and Cd2+ tended to increase the synaptosomal 3H‐DA uptake. 3H‐5‐HT uptake was affected least while that of 3H‐NA showed some diversity. Zn2+, Pb2+ and Sn2+ induced inhibition of 3H‐NA uptake possibly by direct interference with 3H‐NA. As to the spontaneous release of tritiated amines during short incubation from preloaded synaptosomes, Cd2+ decreased that of 3H‐DA at high concentrations but Hg2+, Pb2+, Sn2+ and Zn2+ were ineffective. The results suggest that in vitro the uptake and the release of 3H‐DA are more affected than those of other amines. The inhibitory mechanisms of monoamine uptake may include both direct effects on synaptosomes and indirect ones by interference with the amines themselves.
Pharmacological Modification of Hypertensive Blood‐Brain Barrier Opening
Authors: Johansson Barbro B.
Published: July 2010

Abstract:Acute hypertension was induced by intravenous injection of adrenaline (20 μg/kg) or bicuculline (1.2 mg/kg) in conscious, unrestrained rats with indwelling catheters in aorta and a jugular vein. Three min. after the blood pressure increase, the rats were anaesthetized, and the brains perfusedin situfor 1 min. to remove blood and tracers from cerebral vessels. Evans blue‐albumin and125I labelled serum albumin were used as tracers of the blood‐brain barrier function. Pretreatment with trifluoperazine, thioridazine, imidazole and desipramine significantly reduced the leakage of albumin into the brain compared to non‐treated controls. Acute hypertension enhances pinocytosis activity in cerebral vessels. It is argued that the protective effect of the drugs mentioned may be mediated via an inhibition of the formation of pinocytotic vesicles.
Effect of Amine Uptake Inhibitors on the Uptake of14C‐Bretylium in Intact and Degenerating Sympathetic Nerves of the Rat
Authors: Almgren Olle , Lundberg Dag
Published: July 2010

Abstract:The effect of different amine uptake inhibitors on the accumulation of14C‐bretylium in sympathetically denervated or decentralized salivary glands were studiedin vivorats 11–14 hours after the surgical intervention. The time period chosen is known to be critical for the delaying effect of bretylium on the degeneration transmitter release in sympathetically innervated organs. Cocaine, desmethylimipramine (DMI), protriptyline or reserpine all depressed the uptake of14C‐bretylium in both denervated and decentralized salivary glands, cocaine being the most efficient one. DMI and protriptyline, but not cocaine inhibit the degeneration delaying effect of bretylium, while all three agents inhibit amine uptake at level of the nerve cell membrane. Apparently, bretylium reaches the critical sites of its degeneration delaying action by the axonal amine pump but only a small fraction of the drug entering the degenerating adrenergic nerve terminal is needed at the critical sites to interact with the degeneration processes. The difference between the tricyclic antidepressants on one hand and cocaine on the other with respect to the effect on the degeneration delaying action of bretylium, must depend on some action different from the axonal membrane uptake inhibition. Reserpine which is known not to interfere with the delaying effect of bretylium on the denervation degeneration did reduce the uptake of,14C‐bretylium. This fact seems to indicate that the site of action of bretylium is located outside the adrenergic nerve granules.
Chronic Toxicity of Metrifonate
Authors: Machemer L.
Published: July 2010

Abstract From chronic toxicity studies with metrifonate (identical with trichlorfon) on different animal species, the following conclusion can be reached: 1. There is no conclusive evidence that trichlorfon has a carcinogenic effect. 2. There is no indication that trichlorfon has a significant cumulative toxic effect. 3. There is no confirmation that trichlorfon has a specific effect on liver, blood and haematopoietic organs. 4. The toxicological profile of trichlorfon in the chronic toxicity study consists, on the one hand, in a depression of cholinesterase activity whereby the different animal species differed in their sensitivity. In rats, cholinesterase activity was depressed in serum at dietary levels of 500 p.p.m. and above and also in erythrocytes at a dietary concentration of 1000 p.p.m. In dogs, cholinesterase activity was depressed in serum and erythrocytes at a dietary level of only 200 p.p.m. The Rhesus monkey seemingly is very sensitive because erythrocyte cholinesterase activity is possibly reduced at a daily dose of 0.2 mg/kg per os. On the other hand, induction of an inhibition of spermatogenesis in rats and dogs at a high dose level is discussed, an effect which seemingly is morphologically detectable but nonetheless seems not to affect function as animal experiments have demonstrated.
Effect of Metrifonate on Neuromuscular Transmission
Authors: Le Quesne Pamela M. , Maxwell I. C.
Published: July 2010

Abstract The least detectable effect of acute cholinesterase inhibition (produced by edrophonium) in a normal subject is described. It consists of repetitive activity following the muscle response to a single nerve stimulus. Repetitive activity does not follow a second response at an interval of 30 msec, or 80 msec. There is no change in amplitude of the response to a single stimulus; nor to a second stimulus with the smallest dose of edrophonium. With higher doses of edrophonium the amplitude of the second response is reduced. 55 children were studied during treatment of urinary schistosomiasis with metrifonate (3 doses at 2 weekly intervals). No change in evoked muscle action potential amplitude attributable to treatment was detected. 3 children developed some repetitive activity 6 hours after their third dose, when erythrocyte cholinesterase inhibition was approximately 50%.
Lack of Effect of Opiates on Release of Vasopressin from Isolated Rat Neurohypophysis
Authors: Christensen J. Dencker , Fjalland B.
Published: July 2010

Abstract: Electrical stimulation of rat neurohypophysis in vitro results in a 150‐fold increase in release of vasopressin. Incubation of the isolated lobes with endogenous opiates (Met‐enkephalin, Leu‐enkephalin, β‐endorphin), morphine or naloxone did not change the evoked release of vasopressin significantly. The results obtained do not confirm the hypothesis that endogenous opiates inhibit the release of vasopressin from this preparation.
Effect of p‐p′‐DDE Administeredin Vivoandin Vitroon Ca2+Binding and Ca2+‐Mg2+‐ATPase Activity in Egg Shell Gland Mucosa of Ducks
Authors: Lundholm C. E.
Published: July 2010

Abstract:Thinning of the egg shell is produced by p‐p′‐DDT and DDE in several species of birds. A study was made of the effect of DDE administeredin vitroandin vivoon the Ca2+binding and Ca2+‐Mg2+‐activated ATPase of a homogenate of the egg shell gland of ducks (Anas platyrhynchos var.). The concentration of Ca2+was 1×10−4and that of MgATP 1×10−3M.In vitro, DDE in concentrations of 2–16 μg/ml of incubation medium inhibited the Ca2+‐Mg2+‐activated ATPase in a concentration‐dependent manner, whereas Mg2+‐activated ATPase was not affected by these concentrations. The Ca2+binding by the homogenate was reduced by DDE in the same concentrations. The sodium azide sensitive Ca2+binding was most sensitive.In vivo, DDE administered in a concentration of 40 mg/kg dry weight of the food for 45 days reduced the egg shell index by 18% in comparison to controls. After 45 days of treatment the DDE concentration in the egg shell gland mucosa was 1.20±0.16 μg/g of wet weight, while no DDE was detected in the controls. The Ca2+‐Mg2+‐activated ATPase was reduced by 32%, whereas the Mg2+‐ATPase was not changed. The Ca2+binding by the homogenate was reduced by 29%, the sodium azide sensitive part being most vulnerable. DDE increased the total Ca content of the egg shell gland mucosa by 44%. Since Ca is transported against a concentration gradient between blood plasma and the lumen of the shell gland, it is suggested that DDE, by inhibiting the Ca2+‐Mg2+‐activated ATPase, decreased the Ca translocation over the egg shell gland mucosa.
Studies on Acute Toxicity and Drug Levels of Citalopram in the Dog
Authors: Boeck Vita , Overe Kerstin Fredricson , Svendsen Ove
Published: July 2010

Abstract: Electrocardiographic and haemodynamic changes have been studied in conscious dogs after a sublethal oral dose (20 mg·kg−1) of citalopram. Furthermore, the effects of continuous intravenous infusion of citalopram (10 mg·kg−1 per hour) have been studied in conscious and anaesthetized dogs. The findings have been related to plasma levels of citalopram. Severe convulsive attacks occurred in conscious dogs after infusion of 21.3 or 26.5 mg·kg−1 and after the oral dose. The convulsions were successfully treated with diazepam. In contrast convulsions were not seen in the anaesthetized dogs. They died from respiratory arrest after infusion of 42.2 or 61.3 mg·kg−1. Atrioventricular and intraventricular conduction was unchanged and electrocardiographic changes were negligible. Sinus tachycardia which could be reversed by diazepam and moderate haemodynamic changes were seen. Since no electrocardiographic changes were seen in conscious dogs even during pauses in the convulsive seizure it is concluded that citalopram does not exert cardiotoxic effects in the dog. Good correlation was found between general clinical findings and citalopram levels in plasma. Conscious dogs were exposed to drug levels exceeding those of the average patient by a factor of about 20, while anaesthetized dogs had considerably higher concentrations.