bluuebunny/crossref_metadata_2025 huggingface dataset:
Dextran‐Induced Lowering of Plasminogen Proactivator and Functionally Active High Molecular Weight Kininogen in the Rat
Authors: Berstad Jan , Briseid Kjell
Published: July 2010

Abstract: Incubation of plasminogen‐free rat citrated plasma with acetone (23% v/v) yielded enzyme preparations with high levels of plasminogen activator (PGA) and kininogenase (kallikrein), but with a low concentration of high molecular weight kininogen (HMWK) active as cofactor for kaolin‐induced activation of factor XII. When benzamidine (4.0 mM) was present during acetone activation, a high yield of functionally active HMWK was obtained. Gel chromatography separated PGA into one high molecular weight fraction (HMW‐PGA) without kininogenase and BAEe esterase activity, and one fraction (LMW‐PGA) eluting together with plasma kallikrein. Injection of dextran (100 mg/kg intravenously) reduced the amount of LMW‐PGA to 40%, without altering the concentration of HMW‐PGA, and with only a small reduction of the kininogenase activity.
Pharmacokinetics of Intravenous Metronidazole in Man
Authors: Gjerløff Christian , Arnold Elisabeth
Published: July 2010

Abstract: Metronidazole (500 mg) was infused over 20 min. to five patients. At the end of the infusion blood samples were drawn at brief intervals. After subsequent metronidazole analysis the curve plotted for the elimination of the drug showed a bi‐exponential profile. Mean peak serum concentrations reached 15 μg per ml. At the end of the distribution phase, which was 20 to 30 min. after the infusion, the concentration had fallen to 10 μg per ml. A two‐compartment model was used to calculate the kinetic parameters. The elimination half‐life ranged from 4.7 to 15.8 hours, the total clearance from 43 to 193 ml per min., and the peripheral distribution volume from 41.5 to 79.1 1. The areas under the serum level curves exhibited a four‐fold variation, due to differences in either metabolism or elimination rate.
Binding of β‐Carbolines and Caffeine on Benzodiazepine Receptors: Correlations to Convulsions and Tremor
Authors: Saano Veijo , Airaksinen Mauno M.
Published: July 2010

Abstract: Compounds from both the β‐carboline (BC) and xanthine groups have been suggested to be the natural ligands for benzodiazepine (BZ) receptors. In this study we examined the effects of several BC's and caffeine, 1,3,7‐trimethylxanthine, on the binding of 3H‐flunitrazepam (3H‐FZ) and β‐3H‐carboline‐3‐carboxylic acid ethyl ester (3H‐BCCE) to the BZ receptors of rat and mouse brain. In mice, convulsion‐producing doses of caffeine (120 mg/kg intravenously) and harmane (30 mg/kg intravenously) lowered the specific binding of 3H‐FZ in vivo by 12–31%. A tremorogenic dose of harmaline (30 mg/kg intravenously) increased binding by 31%. Caffeine and harmane also slightly decreased the in vivo binding of 3H‐BCCE, a compound that binds preferentially to the cerebellar type of BZ receptors. Harmaline stimulated the binding of 3H‐BCCE only in the forebrain. Both harmaline and harmane increased by 41–111% the amount of 3H‐BCCE that was distributed to the brain. In vitro BC's and caffeine displaced 3H‐FZ from receptors in the rat brain with various Ki values (4.7 to 206.9 μM). The antagonism for BZ binding was competitive and in Scatchard analysis produced linear plots. Exceptions were harmaline and caffeine in the forebrain: both exhibited curvilinear plots for 3H‐FZ binding. Harmaline increased the binding, and caffeine decreased it by altering the affinity of a subgroup of BZ receptors. In the hindbrain both harmaline and caffeine inhibited binding and produced linear plots. BC‐induced tremor and convulsions unveil a large number of spare receptors in the brain, and these seem to be of the cerebellar type of BZ receptors. In addition, our results show that tremorogenic and convulsive BC's act differently on BZ receptors: during harmaline‐induced tremor the affinity of some BZ receptors is increased, while harmane‐induced convulsions are connected to direct occupation of BZ receptors.
Actions of Theophylline, Terbutaline, and Ipratropium Bromide Alone and in Combinations on the Methacholine Induced Bronchoconstriction in Rats
Authors: Salonen R. O. , Mattila M. J. , Edholm L.‐E.
Published: July 2010

Abstract: Rats under pentobarbitone anaesthesia, pancuronium relaxation and artificial ventilation with constant volume, were given methacholine (MeCh) 4, 6, and 9 μg intravenously at 2 min. intervals; the rise in intratracheal pressure indicated bronchoconstriction. The heights of peak responses (PIPR), response areas (RA), and blood pressure and heart rate were recorded, and theophylline (THEO) concentrations in plasma and lung tissue were measured. THEO (5, 10, or 20 mg/kg intravenously) proved a weak bronchodilator agent with pronounced effects on circulation. Terbutaline (TER) (10, 20, or 40 μg/kg intravenously) shifted dose dependently the airways MeCh dose‐response curves to the right, with minor stimulation of the heart. THEO 5+TER 20, and THEO 20+TER 20 enhanced the bronchodilator action of each other in an additive manner. Ipratropium bromide (IPRA) (5 μg/kg intravenously) eliminated MeCh bronchoconstriction without any inhibition of MeCh bradycardia and with partial inhibition of MeCh hypotonia. THEO 20+IPRA 0.5 provided a supra‐additive bronchodilation. Injection of TER 20 promoted the penetration of THEO into the lungs thus increasing THEO concentrations in the lung tissue. The present results suggest that in this animal model combinations of low doses of THEO with TER/IPRA provide enhanced bronchodilation but reduced cardiovascular effects, in comparison with single therapy. Further, a pharmacokinetic interaction between THEO and a beta2‐agonist was evident within certain doses.
Inhibitory Effects of Different Retinoids (Vitamin A Analogues) on the Stimulated Rat Liver Guanylate Cyclase Activity
Authors: Rydell Ewa L. , Axelsson Krister L. , Andersson Rolf G. G. , Wikberg Jarl E. S.
Published: July 2010

Abstract: Vitamin A and its analogues show the ability to prevent malignant cell transformation on induction with different carcinogens, such as nitrosamines. Cyclic GMP has been proposed as a positive modulator of malignant cell growth and the cGMP‐forming enzyme guanylate cyclase is strongly stimulated by e.g. nitrosamines. In this study, we found that retinylacetate and retinal were very potent inhibitors of the stimulated guanylate cyclase. When a series of structurally different retinoids were tested in the same system, a wide range of inhibitory activity on guanylate cyclase was found for the different retinoids with some being completely ineffective. The most potent inhibitor was retinylacetate. Furthermore, the inhibitory profile of the retinoids on the guanylate cyclase did not seem to correlate to their in vivo activity as antineoplastic agents, as described in the literature. We therefore conclude that there does not exist a general connection between the anticancer activity and the guanylate cyclase inhibition of the retinoids. However, it can not be excluded that the guanylate cyclase inhibition might be of importance for the antineoplastic activity for some of the retinoids.
Placental Transport of the Non‐metabolisable α‐Aminoisobutyric Acid in Guinea‐pigs Given a Commercial Chlorobiphenyl Preparation or a Defined, Pure Chlorobiphenyl
Authors: Kihlström Ingemar
Published: July 2010

Abstract: The placental transfer of the non‐metabolisable α‐aminoisobutyric acid was studied by means of a perfusion technique in pregnant guinea‐pigs given the commercial chlorobiphenyl preparation, Clophen A50 (C‐A50) or pure 2,2′,4,4′,5,5′‐hexachlorobiphenyl (HCB), during different periods of gestation. It was shown that a total dose of 30 mg of HCB given during the latter part of gestation (day 45 to 61) decreased amino acid transport, while 30 mg of C‐A50 did not. At a dose of 30 mg daily given from day 28 to day 61, again only HCB decreased the amino acid transfer. An amount of 60 mg C‐A50 was required to reduce this transport. The concentration of the amino acid in blood from foetuses remaining in the uterus was significantly increased when the dams were given 60 mg of C‐A50, indicating a reduced foetal uptake of the amino acid. It is suggested that the decreased placental transfer of the amino acid is dependent on physio‐chemical interactions (e.g. caused by hydrophobic properties) between the chlorobiphenyls and the NaK‐ATPase enzyme complex which is involved in amino acid transport.
Embryotoxicity of Industrial Chemicals on the Chicken Embryo: Thiourea Derivatives
Authors: Korhonen Aila , Hemminki Kari , Vainio Harri
Published: July 2010

Abstract: Six thioureas: 1,3‐diphenylthiourea (DPTU), 1,3‐dibutylthiourea (DBTU), tetramethylthiourea (TEMTU), trimethylthiourea (TRIMTU), 1,3‐diethylthiourea (DETU), and 1,3‐ethylenethiourea(ETU), were tested, in addition to carbon disulfide, on three day chicken embryos for embryotoxicity. The parameters measured were early deaths, recorded within two days of injection, late deaths of malformed embryos, late deaths of non‐malformed embryos, and malformed survivors. The order of total embryotoxicity decreased as follows DBTU>DPTU>TEMTU>TRIMTU>DETU>ETU. The range for ED50 values for total embryotoxicity was from 0.28 (DBTU) to 4.5 (ETU) μmol/egg. DBTU caused early deaths but no malformations. TEMTU and DPTU were the most potent teratogens.
Effect of Styrene on Glutathione Content and some Xenobiotic Metabolizing Enzymes of Rat Kidney
Authors: Das Mukul , Srivastava Satya Prakash , Seth Prahlad K.
Published: July 2010

Abstract:The effect of orally administered styrene (450 mg/kg and 900 mg/kg body weight for 7 consecutive days) on activity of microsomal mixed function oxidase, glutathione‐S‐transferase and glutathione content of rat kidney was studied. Styrene treatment caused a significant increase in aryl hydrocarbon hydroxylase, aniline hydroxylase, ethylmorphine‐N‐demethylasc and benzphetamine‐N‐demethylase and a decrease in glutathione‐S‐transferase activity at both dose levels. A decrease in glutathione content was noticed only at the higher dose (900 mg/kg). The results suggest that styrene could affect its own detoxification process in kidney tissue.
Qualitative Differences between the Inotropic Responses in Rat Papillary Muscles to α‐Adrenoceptor and β‐Adrenoceptor Stimulation by both Noradrenaline and Adrenaline
Authors: Skomedal T. , Osnes J.‐B.
Published: July 2010

Abstract:Mammalian heart has obviously both α‐ and β‐adrenergic inotropic mechanisms, and stimulation of these two mechanisms by appropriate agonists lead to qualitatively different inotropic responses. This difference can serve to recognize the two adrenergic inotropic effects. In order to explore if the endogenous catecholamines, noradrenaline and adrenaline, could activate both these mechanisms, and if so, to characterize them qualitatively and quantitatively, the mechanical responses in electrically driven rat left ventricular papillary muscles were examined in the absence or presence of appropriate receptor blockade. Isometric tension (T), rate of rise and decline of tension (first derivative = T) and rate of transition from tension rise to tension decline (negative part of second derivative=T) were recorded. α‐Adrenergic and β‐adrenergic inotropic effects were demonstrated both for noradrenaline and adrenaline. Maximal β‐adrenoceptor stimulation (agonist in the presence of an α‐adrenoceptor blocker) caused a small increase in Tmax, intermediate increases in T'maxand T'min, and a considerable increase in Tmin(β‐typeeffect). Maximal α‐adrenoceptor stimulation (agonist in the presence of a β‐adrenoceptor blocker) increased all parts of the contraction‐relaxation cycle by about the same degree (TminTminT'maxTmaxα‐typeeffect). While β‐adrenoceptor stimulation gave a dose dependent and pronounced increase in the ratio Tmin/Tmax(relaxation‐onset index), α‐adrenoceptor stimulation decreased it to subcontrol values. The time course of the response to the α‐adrenoceptor stimulation was characterized by a transient decrease in all qualities followed by an increase which reached maximum at 4–5 min. β‐Adrenoceptor stimulation gave a monophasic inotropic response which developed in the course of 1–2 min. Both agents alone gave a monophasic response with the characteristics of a β‐typeeffect (i.e. relative maximal increase of TminTminTmaxTmax), and a marked increase in the relaxation‐onset index (Tmin/Tmax). Thus the β‐adrenergic inotropic component was the dominating one when the amines were used alone. The two different response patterns probably reflect a dual mechanism of action of the endogenous catecholamines: the β‐adrenergic component which is dependent upon an increase in cyclic AMP levels and the α‐adrenergic component which is independent on cyclic AMP.
The Influence of the Sweetening Agent on the Oral Absorption of Penicillin V
Authors: Eriksson Margareta , Bolme Per , Finkel Yigael
Published: July 2010

Abstract: Plasma concentrations of penicillin V were determined following oral administration in children of mixtures containing different sugars as sweetening agents. Significantly higher peak plasma concentrations and area under the curve were found with sacharose than with sorbitol. Mixtures containing fructose gave intermediate values.
Effect of Time and Dose on Angiotensin Converting Enzyme during Captopril Treatment in the Rat
Authors: Forslund Terje
Published: July 2010

Abstract: The effect of treatment time and dose of captopril with regard to angiotensin converting enzyme (ACE) in serum, lungs and kidneys of the rat were studied. Normotensive Wistar rats were treated with a constant dose of captopril (0.2 mg/ml) during various time periods. In a second study rats were treated with different captopril doses (6.25 μg, 12.5 μg, 25 μg, 50 μg, and 200 μg/ml water) during three weeks. Serum ACE activity and pulmonary and kidney plasma membrane ACE concentrations were measured in both studies. Captopril treatment resulted in a rapid decrease of ACE in pulmonary and kidney plasma membranes and a simultaneously increase of serum ACE activity during the first day of treatment. This was followed by increased membrane concentrations of ACE in the lungs and return to normal ACE concentrations in membranes of kidneys, presumably due to increased ACE biosynthesis. Serum ACE activity continued to increase during the whole study. Serum ACE activity increased in a dose dependent manner during treatment with different captopril doses. Increased plasma membrane ACE concentrations were not observed in the rats treated with captopril at doses below 200 μg/ml water.
Regeneration of Rat Mast Cells after Histamine Secretion: Changes in Histidine Decarboxylase Activity and Heparin Synthesis
Authors: Chakravarty Nirmal
Published: July 2010

Abstract:Histidine decarboxylase activity in rat peritoneal mast cells is depressed temporarily after histamine secretion induced by antigen in sensitized cells or by compound 48/80. Recovery starts after 10 min. and the enzyme activity is completely restored in about 1–2 hours. There is no stimulation of the enzyme activity upto 4 hours after the exposure to the releaser. The enzyme activity shows more prolonged depression after histamine release induced by inonophore A23187 probably because of leakage of the cytoplasmic enzyme. Inspite of the loss of some granules from the mast cells, histamine uptake is enhanced during the first two hours apparently due to the uptake into the granule matrices in the compound exocytotic vacuoles. These granules remain within the cell, but the release of endogenous histamine to the extracellular fluid during secretion makes the binding sites available for histamine uptake. There is no indication of increased histamine production during the period of observation, viz. up to 6 hours after the secretion. The heparin content is reduced during the first two hours due to the loss of granules from the cells, but this is restored during 4–6 hours by increasing synthetic activity. Heparin synthesis is reduced to about 40% of the normal value during the first 4 hours, and is practically restored to normal during 4–6 hours.
Affinity of Drugs for Cytochrome P‐450 Determined by Inhibition of p‐Nitrophenetole O‐Deethylation by Rat Liver Microsomes
Authors: Jørgensen Lars , Johansen Torben
Published: July 2010

Abstract:The rate of conversion of p‐nitrophenetole to p‐nitrophenol by rat liver microsomes was studied. Inhibition of the reaction by CO and by SKF 525A and the absolute dependence on NADPH and oxygen indicate that cytochrome P‐450 catalyzes the reaction. The apparent Kmfor oxygen was 0.07 μM. Furthermore, cytochrome b5seemed to be involved in the formation of p‐nitrophenol. The effect on p‐nitrophenol formation of drugs known to be involved in drug interaction in clinical practice was studied. There was a competitive inhibition by phenytoin (inhibitor constant, Ki, 30 μM), disulfiram (Ki, 2 μM) and chloramphenicol (Ki, 20 μM), whereas a mixed‐type inhibition by isoniazid was observed (Kis, 1,3 mM and Kii, 10,6 mM).
Organophosphate Metasystox‐induced Increment of Lipase Activity and Lipid Peroxidation in Cerebral Hemisphere: Diminution of Lipids in Discrete Areas of the Rat Brain
Authors: Islam Fakhrul , Tayyaba K. , Hasan Mahdi
Published: July 2010

Abstract: The effects of the pesticide, metasystox (O,O‐dimethyl‐S‐2 or Metasystor® (ethylsulphinyl) ethylthiophosphate), on various lipid fractions in the discrete areas of the brain were studied. The daily intraperitoneal administration of 4 mg/kg body weight of metasystox for 10 days has depleted the levels of total lipids, phospholipids, cholesterol, esterified fatty acids and gangliosides in cerebral hemisphere, cerebellum, brain stem and spinal cord. But the lipase and lipid peroxidation measured in the cerebral hemisphere were significantly increased. It is possible that the inhibition of the lipid levels in the discrete areas of the brain may be due to the increase activity of lipase and lipid peroxidation.
Effect of an Acute Dose of Ethanol on Lipid Peroxidation and on the Activity of Microsomal Glutathione S‐Transferase in Rat Liver
Authors: Sippel H. W.
Published: July 2010

Abstract: Acute ethanol administration (1.5 g/kg) to fasted rats resulted in a small but significant increase in the content of conjugated dienes in the microsomal fraction of liver. Treatment with 4‐methylpyrazole prior to ethanol ingestion was able to reduce the ethanol‐induced lipid peroxide formation (measured as conjugated dienes). No depletion of glutathione occurred within the first 2 hrs following ethanol administration by which time lipid peroxide formation is well established. The ethanol‐induced inhibition of N‐ethylmaleimide‐stimulated microsomal glutathione S‐transferase activity correlates positively to the concentration of conjugated dienes in the microsomal fraction of liver.
Enhancement of 5‐Hydroxytryptamine Uptake in Rabbit Hypothalamic Synaptosomes but not in Blood Platelets by Zinc and Lead ex Vivo
Authors: Komulainen Hannu
Published: July 2010

Abstract: Lead (0.2%), zinc (0.5%) or their combination was given to rabbits as acetate salts in drinking water for 2 or 4 weeks. Cerebral Pb increased within exposure time but the increase of Zn was marginal when given alone. After combination of Pb+Zn, blood Pb increased but Zn decreased as compared to the administration of the single metal alone. Concurrently brain Pb increased but remained at a lower level as compared with sole Pb administration while brain Zn did not differ from controls. The uptake of 5‐hydroxytryptamine (5‐HT) into hypothalamic synaptosomes increased 70–85% with Pb, Zn and Pb+Zn after 2 weeks and 93% with Zn and 76% with Pb+Zn after 4 weeks. Dopamine uptake into striatal synaptosomes did not change. Zn decreased endogenous noradrenaline concentrations by 21% and Pb+Zn that of 5‐HT by 36% in the striatum. Pb+Zn decreased cortical dopamine concentrations by 26%. Concurrently, 5‐HT uptake in blood platelets, platelet numbers and their content of endogenous 5‐HT did not change significantly. These results indicate that high Zn and Pb have parallel effects on 5‐HT uptake in hypothalamic synaptosomes and their combination may be neurochemically more toxic than the individual metals. The increase of 5‐HT uptake in hypothalamic synaptosomes but not in blood platelets requires further methodological work to explain the differences between synaptosomes and platelets.
Differentiated cell and organ culture in toxicity testing.
Authors: Balls M. , Clothier R.
Published: July 2010

Abstract The safety evaluation of new chemicals involves a range of investigations, including acute and sub‐acute toxicity testing, long‐term toxicity testing, studies on mutagenicity, carcinogenicity, and reproductive toxicity, and special investigations involving the interaction of the chemical under test with particular parts of the body, such as the skin or the nervous system. We shall consider the potential role of differentiated cell and organ culture in toxicity testing, and the criteria available for assessing cell viability, damage, and death, with a view to establishing whether such methods could be used for determining the relative acute toxicities of chemicals. We shall also consider methods for studying the effects of chemicals on general and specific aspects of cell structure and function, including liver cell and organ cultures both as primary targets themselves susceptible to damage and as providers of metabolically activated compounds able to affect other cells and tissues.
A Comparative Study of the Pharmacodynamic Effects of Nimodipine and Nifedipine in the Isolated Spontaneously Beating Rabbit Heart
Authors: Nielsen‐Kudsk F. , Askholt Jan , Jensen Per Hyldgård
Published: July 2010

Abstract:Myocardial effects of the calcium antagonistic drugs nimodipine and nifedipine were comparatively studied in retrogradely perfused rabbit hearts at stepwise increasing drug concentrations in the perfusion liquid within the range of 1–60 ng ml−1. Pharmacodynamic steady states developed slowly within about 25 min. at each concentration level. Nimodipine produced in comparison with nifedipine a progressive and very marked negative chronotropic effect and caused simultaneously a very pronounced increase in the QT‐interval. The potency of nimodipine with regard to these effects were about 10 times that of nifedipine. The PQ‐interval was only increased significantly at the two highest concentrations of nimodipine. Both drugs caused a pronounced inhibition of myocardial contractility as judged from the decrease in contraction amplitude and rate of contraction. Myocardial efficiency expressed as the ratio of contraction‐rate to oxygen consumption decreased progressively and highly significantly with increasing drug concentrations. The relative potency between nimodipine and nifedipine with regard to the negative inotropic effects was only about 1.7. Increasing exposure to nimodipine produced a progressive decrease of the mean coronary flow‐rate, whereas nifedipine initially caused an increase followed by a terminal decrease to the initial flow‐rate level.
Thioamides as False Melanin Precursors: Studies in Murine Melanomas
Authors: Olander K. , Larsson B. , Dencker L.
Published: July 2010

Abstract: Melanotic melanomas show a high rate of melanin synthesis. Foreign substances that are accepted as precursors in the formation of melanin may therefore be useful in the diagnosis and therapy of malignant melanotic melanomas, if labelled with suitable radionuclides. We have earlier reported that 2‐thiouracil is incorporated in melanotic melanomas, apparently as a false melanin precursor. In the present study it is shown that methimazole and 5‐iodo‐2‐thiouraciI are as well accepted as melanin precursors. 5‐Iodo‐2‐thiouracil is of special interest, since iodine has many clinically useful radioisotopes. The chemical properties that characterize substances which are incorporated as false precursors into melanin are discussed. A free sulfur ligand of the thioamides (2‐thiouracil, 5‐iodo‐2‐thiouracil, methimazole and thiourea are all incorporated into melanin) seems to be essential and the link between these substances and the melanin. Uracil (which lacks sulfur) and 2‐benzylthiouracil (where the sulfur is blocked with a benzyl group) do not attach to melanin. Our conclusion therefore is that the thioureylene structure is the smallest common molecular fragment of the false melanin precursors.
Pharmacokinetics of the γ‐Aminobutyric Acid Agonist THIP (Gaboxadol) Following Intramuscular Administration to Man, with Observations in Dog
Authors: Madsen Søren Munk , Lindeburg Thimm , Følsgård Søren , Jacobsen Erik , Sillesen Henrik
Published: July 2010

Abstract: The pharmacokinetics of the γ‐aminobutyric acid (GABA) agonist, THIP (Gaboxadol) has been studied following intramuscular administration of 10 or 20 mg THIP‐monohydrate to six healthy human volunteers. Additional experiments with special reference to the possible occurrence of non‐linear kinetics and to estimation of the efficiency of absorption were carried out in three beagle dogs. As estimated from the dogs, absorption of THIP from the site of injection was efficient (F=0.94±0.16, mean±S.D., in 8 experiments). The time course of the THIP serum concentration was in all experiments adequately described by an open 1‐compartment linear model. In most individual experiments a near maximum concentration was present at 15 or 10 min. after the administration to man and dog, respectively. In some subjects and dogs an uncertain relation was found between dose and the time integral of the THIP serum concentration, but the mode of variation did not suggest deviations from first‐order kinetics at high doses or concentrations. The rate constant of elimination was estimated to 0.50±0.13 hr−1 and 0.52±0.13 hr−1 following injection of a 10 or 20 mg dose, respectively, to man (mean±S.D., n=6), and similar values were obtained from the dogs.
Inhibition of the Excitatory Non‐adrenergic, Non‐cholinergic Neurotransmission in the Guinea Pig Tracheo‐bronehial Tree Mediated by α2‐Adrenoceptors
Authors: Grundström Nils , Andersson Rolf G. G. , Wikberg Jarl E. S.
Published: July 2010

Abstract: Guinea pig main bronchi were studied in vitro for the presence of motor innervation. Field stimulation of the main bronchi revealed that besides the excitatory cholinergic component a slow and atropine resistant contraction similar to that previously found in the hilus bronchi (Grundström et al. 198 la) was present also at this level of the airways. This slow contraction was blocked by tetrodotoxin whereas it was left unaffected by a number of conventional antagonists (i.e. atropine, guanethidine, propranolol, yohimbine and prazosin) suggesting that it was due to activation of non‐adrenergic, non‐cholinergic neurones. In the presence of a β‐adrenoceptor blocking drug, noradrenaline inhibited the slow contractions induced by field stimulation in both the main and hilus bronchi. By contrast, contractions elicited by histamine were left unaffected by noradrenaline. In order to characterize the receptor for noradrenaline the effects of α1‐ and α2‐adrenoceptor blockers were evaluated. The results indicate that in the guinea pig bronchi noradrenaline inhibits nonadrenergic, non‐cholinergic neurotransmission by acting on prejunctional α1‐adrenoceptors.
Tissue Distribution of Angiotensin Converting Enzyme in the Rat: Effect of Captopril Treatment
Authors: Forslund Terje , Kouvonen Ilkka , Fyhrquist Frej
Published: July 2010

Abstract: Effect on different tissues with regard to angiotensin converting enzyme during captopril treatment in the rat was studied. Male Wistar‐Kyoto rats (n = 9) were treated during four weeks with captopril dissolved into the drinking water at the dose 30 mg/kg/day. Control rats (n = 9) had water only. Serum angiotensin converting enzyme (ACE) activity increased three‐fold during captopril treatment, and ACE of purified pulmonary plasma membranes increased about 64% (P<0.001) compared to untreated rats. ACE activity of membrane fractions of other tissues studied i.e. testicles, epididymes, kidneys, and small intestine brush border did not increase similarly during captopril treatment. The highest amounts of ACE was demonstrated in epididymes, but captopril did not produce increased amounts of ACE in the epididymes. The main source of increased serum ACE activity during captopril treatment appeared to be in the pulmonary tissue.
Toluene‐induced Decrease in Rat Plasma Concentrations of Tyrosine and Tryptophan
Authors: Voog Lennart , Eriksson Tomas
Published: July 2010

Abstract: The organic solvent toluene is demonstrated to cause a decrease in rat plasma concentrations of tyrosine and tryptophan both after intraperitoneal injections and after inhalation. Tyrosine and tryptophan are precursors to neurotransmitters and are transported from plasma into the brain. As the concentrations of these amino acids in plasma could influence the monoamine synthesis in the brain, this phenomenon might be of importance for the pathophysiology behind solvent‐induced effects on brain function.
Haemolytic Activity of Copper as Influenced by Chelating Agents, Albumine and Chromium
Authors: Aaseth Jan , Skaug Vidar , Alexander Jan
Published: July 2010

Abstract: The haemolytic activity of CuSO4 (0.3 mM) in vitro was reduced in the presence of albumine (5‐20 g/1). The presence of D‐penicillamine, triethylene tetramine or dimercaptosuccinic acid (0.3 mM) also reduced the copper‐induced haemolysis, whereas 2,3‐dimercaptopropane‐1‐sulphonate increased the cytolysis. N‐ethylmaleimide (NEM) in appropriate concentrations (1 mM), as well as chromic chloride (0.3 mM), reduced the copper‐induced haemolysis. Higher concentrations of NEM (2 mM) were ineffective. The results may provide helpful suggestions as regarding the clinical treatment of copper poisoning and Wilson's disease. The results may also be helpful for the understanding of the mechanisms of haemolysis associated with copper intoxication in vivo.
Attenuation of the Post‐decapitation Convulsions after Repeated Treatment of Rats with Desipramine, Imipramine and Maprotiline
Authors: Archer Trevor , Ross Svante B. , Minor Bruce G.
Published: July 2010

Abstract:The effects of repeated treatment of rats with the antidepressant or potential antidepressant agents alaproclate, citalopram, clomipramine, desipramine, imipramine, maprotiline, mianserin and zimeldine on the convulsions released by decapitation were examined. The noradrenaline uptake inhibitors desipramine, imipramine and maprotiline increased significantly the latency of onset of the post‐decapitation convulsions (PDC's) after repeated administration of 10 μmol/kg orally twice daily, or 66 μmol/kg orally once daily (desipramine), for 15 days. The duration of the PDC's was slightly prolonged by these agents. A single acute dose of desipramine (20 mg/kg) administered at various time intervals before decapitation (1 to 24 hours) had no effect on the PDC's nor did repeated treatment with the other compounds examined, alaproclate, citalopram, clomipramine, mianserin and zimeldine, have any effect upon the PDC latency. The results are interpreted as evidence for noradrenaline receptor subsensitivity following chronic treatment.
A Comparison of the Binding Characteristics of the β‐Adrenoceptor Antagonists3H‐Dihydroalprenolol and125I‐Iodocyanopindolol in Rat Liver
Authors: Sandnes D. , Westergren T. , Sand T. E. , Sager G. , Refsnes M. , Christoffersen T. , Jacobsen S.
Published: July 2010

Abstract:The binding characteristics of3H‐dihydroalprenolol and125I‐iodocyanopindolol have been compared in a particulate fraction from regenerating rat liver. When total3H‐dihydroalprenolol binding and inhibition of total3H‐dihydroalprenolol binding by (‐)isoprenaline, (‐)alprenolol and (±)cyanopindolol was investigated, it was found that all agents were bound to two classes of saturable binding sites. In the inhibition studies, the presence of two binding components was not obvious until the data were transformed into Hofstee plots and these were decomposed, except in the case of (±)cyanopindolol. Only (±)cyanopindolol was found to distinguish clearly between the two saturable binding sites identified by3H‐dihydroalprenolol, as indicated by a broad plateau in the inhibition curve. When125I‐iodocyanopindolol was used as radioligand, only one saturable binding site was identified, even in the presence of less selective inhibiting ligands. The lower affinity component of3H‐dihydroalprenolol binding could be inhibited by 10 μM phentolamine. However, binding experiments with3H‐prazosin indicated that the lower affinity component was not identical with the alpha‐adrenoceptor. Phentolamine did not influence125I‐iodocyanopindolol binding. Thus, due to its higher specific activity and a high degree of selectivity,125I‐iodocyanopindolol appears to be the ligand of choice.
A Study on Benzodiazepine Receptor Binding in Audiogenic Seizure‐susceptible Rats
Authors: Tacke Ulrich , Bræstrup Claus
Published: July 2010

Abstract:Benzodiazepine receptors were investigated in the cerebral cortex, the hippocampus, the brainstem, and the cerebellum of audiogenic seizure (AGS)‐susceptible and seizure‐resistant (ER) control rats. In AGS‐susceptible rats of Sprague‐Dawley descent, muscimol (10‐6M and 3 × 10‐5M) activated the binding of3H‐diazepam (0.4 nM) significantly less than in ER‐rats. This finding may be strain selective, since it was not observed in AGS‐susceptible rats of Wistar descent. Specific binding of the convulsant benzodiazepine receptor ligand methyl 6,7‐dimethoxy‐4‐ethyl carboline‐3‐carboxylate (3H‐DMCM), the benzodiazepine receptor ligand3H‐diazepam and the chloride channel directed cage convulsant t‐butylbicyclophosphorothion‐ate35S‐TBPS were not significantly changed in AGS‐susceptible as compared to control rats. Our findings indicate that a disturbance at the level of the benzodiazepine receptor/GABA receptor/chloride channel complex is not a likely general aetiological factor for audigenic seizures in rats.
Sympatho‐adrenal mechanisms and the antihypertensive response to thiazide diuretics
Authors: Hjemdahl Paul
Published: July 2010

Abstract:Thazide diuretics lower the blood pressure during long‐term treatment by reducing the peripheral vascular resistance. This seems to be related to the natriuresis rather than to a direct vasodilating effect of the thiazides. There is evidence that the volume depletion caused by thiazide treatment initially triggers an increase in sympathetic nerve activity, which may account for initial increases in vascular resistance. Although both responses subside during long‐term treatment, there is no evidence showing a causal relationship between these changes. The long‐term hemodynamic adaptation to thiazide treatment may be related to altered cardiovascular reflexes. Changes in sympathetic nerve activity and reduced vascular sensitivity to noradrenaline may contribute to the adaptation. An analysis of the relative importance of these mechanisms requires further studies comparing the time courses for various effects in respondcrs and non‐responders to the treament.
Comparison of the Calcium–Antagonistic Effects of Terodiline, Nifedipine and Verapamil
Authors: Larsson‐Backström Carin , Arrhenius Eva , Sagge Kristina
Published: July 2010

Abstract: Studies were carried out on the Ca–antagonistic effects of terodiline and its enantiomers on the potassium–stimulated mesenteric and coronary arteries, on the spontaneous myogenic activity and norepinephrine– and acetylcholine–induced contractions of the protal vein and on electrically stimulated papillary muscle. The effects were compared with those of the Ca–antagonists, nifedipine and verapamil. Terodiline is relatively weak as a Ca–antagonist, having IC50–values between 5 × 10–6and 2 × 10–5 M for all the tissues studied. Nifedipine is the most potent Ca–antagonist on vascular smooth muscle (IC50 3–6 × 10–9M), but is considerably less potent on the papillary muscle (IC50 10–7 M). Verapamil is most potent on the papillary muscle (IC50 7 × 10–8M) and the portal vein (IC50 6 × 10–8M), but is 10 times less potent on the mesenteric and coronary arteries (IC50 3–5 × 10–7 M). Nifedipine is 1000 times and verapamil and (–)–terodiline 10 times more potent on the slow component of the K–induced contraction while (±)– and (+)–terodiline are almost as active on the fast as on the slow component of K–induced contractions on the mesenteric artery. Furthermore, (±)– and (+)–terodiline are 10 times more potent in antagonizing acetylcholine– and norepinephrine–induced contractions, whereas (–)–terodiline is equally potent and nifedipine and verapamil are 10 times more potent in blocking the myogenic activity of the portal vein. On the Ca2+–depleted portal vein the contractions induced by K+, together with Ca2+, were antagonized by terodiline, nifedipine and verapamil. However, nifedipine and verapamil, but not terodiline, in concentrations which blocked the maximal norepinephrine–induced response in non–depleted muscle, antagonized the contractions induced by norepinephrine together with Ca2+ in the Ca2+ depleted portal vein. These results show that terodiline blocks the uptake of Ca2+ and, in addition, blocks the utilization of some intracellular stores of Ca2+
The Effect of Thiabendazole on Pain Threshold
Authors: Gomaa A. A.
Published: July 2010

Abstract:Thiabendazole significantly increased the reaction time to thermal stimulus. However, in mice treated with morphine, the reaction time was not in any way different from those treated with combined doses of thiabendazole and morphine. Thiabendazole was found to have an antinociceptive action. The protective dose for 50% of animal (ED50) against p–benzoquinone–induced writhing reflex was found to be 310 mg/kg. The ED50 for aspirin alone was 140 mg/kg. When the ED50 of aspirin was determined in combination with different dose levels of thiabendazole, it showed a marked reduction in the values reaching 50 mg/kg, when 300 mg of thiabendazole was used in combination. Toxicological studies revealed that the oral LD50 for thiabendazole in mice was 2200 mg/kg, and when combined with 140 mg/kg of aspirin, the LD50 was reduced to 900 mg/kg. These findings indicate that thiabendazole possesses an analgesic activity which is potentiated by aspirin, though aspirin was found to significantly enhance its toxicity
Studies on Low Dose Sub–acute Administration of Soman, Sarin and Tabun in the Rat
Authors: Dulaney M. D. , Hoskins B. , Ho I. K.
Published: July 2010

Abstract:The effects of low–dose administration of the organophosphate cholinesterase inhibitors, soman, sarin and tabun, on growth rates over 85 days were studied in rats. Acetylcholinesterase (AChE) activity was determined in the striatum and the remainder of the brain 24 hrs following the last exposure to these agents. Further, the cumulative mortality of daily administration of several doses of soman, sarin and tabun for 25 days was studied. The animals treated with 25 μg/kg of soman or sarin for 85 days demonstrated reduced growth rates which returned to control levels after 30 days. The animals which received 50 μg/kg of sarin also grew at reduced rates which returned to control levels after 35 days, while the tabun–treated (100 μg/kg) animals required 38 days to return to control growth rates. The striatal AChE activity of the soman–treated group was reduced to 36% of control while the AChE activities of the high–dose sarin–treated group were reduced to 66% of control. The striatal AChE activity of the tabun–treated group was only 13% of control. It is suggested that growth rates may be used to monitor the development of tolerance to lowdose administration of organophosphate cholinesterase inhibitors
Enprofylline and Theophylline on Small Human Placental Arteries: Studies of in Vitro Effects and Mode of Action
Authors: Nielsen‐Kudsk Jens Erik
Published: July 2010

Vascular effects of theophylline and enprofylline, a novel xanthine derivative lacking adenosine receptor antagonism, were studied comparatively in tubular preparations of small human placental arteries mounted in an isometric myograph. Both xanthines produced concentration‐dependent (10−7‐3 × 10−3 M) relaxation of arteries contracted by PGF2α or PGE2 in both normal Ca2+‐medium and in Ca2+‐depleted medium. Enprofylline was about three times more potent than theophylline. Also in vasopressin‐contracted arteries enprofylline was a more potent vasodilator in both media. In contrast the xanthines were equally potent in relaxation of the tonic as well as the phasic part of a K+‐induced contraction, but less potent than in relaxation of PG‐induced contractions. Propranolol, phentolamine, atropine, indomethacin or tetrodotoxin did not influence the xanthine relaxations. It is concluded that the theophylline‐induced relaxation of small human placental arteries is not due to adenosine receptor antagonism. A common important mechanism of action, in which enprofylline is more potent than theophylline, seems to be interference with intracellular Ca2+‐binding/mobilisation processes. Some decrease in cellmembrane Ca2+‐permeability produced by the xanthines seems to take part in the mechanism of relaxation.
Tests for Local Toxicity of Intramuscular Drug Preparations: Comparison of in Vivo and in Vitro Methods
Authors: Svendsen O. , Højelse F. , Bagdon R. E.
Published: July 2010

Different concentrations of aqueous preparations of metoclopramide, gaboxadol, cis(Z)‐clopenthixol, digoxin and chlorpromazine and of cis(Z)‐clopenthixol acetate in Viscoleo have been tested for local toxicity after intramuscular injection in rabbits. The weight of macroscopically changed muscle tissue isolated 3 days after injection was determined. In addition, homogenized injection site muscle tissue was analysed for creatine kinase (CK) activity and by comparison with the CK activity of contralateral muscle tissue, the amount of injection site muscle tissue totally depleted for CK activity was calculated. The substances have also been tested for in vitro toxicity. The concentrations of the substances which caused 100% haemolysis of human erythrocytes or minimal cytotoxicity in cell culture assays using MRC‐5 fibroblasts were estimated. Metoclopramide and gaboxadol caused no or only minimal local muscle damage in the rabbits. Metoclopramide caused local bleeding. The four other substances caused concentration‐dependent muscle damage. Although there was some deviations, the two in vitro tests reflected reasonably well the in vivo findings. The results of this study suggest that the in vitro tests employed can be useful as screening tests for local toxic effect of intramuscular drug preparations. However, further studies are required before conclusion as to predictability can be drawn. The in vitro methods are inexpensive and quick, especially the haemolysis test.
Effects of Acute and Short‐Time Antibiotic Treatment on Renal Lithium Elimination and Serum Lithium Levels in the Rat
Authors: Lassen Erik
Published: July 2010

Male Wistar rats received a single stomach load (10 ml/kg) of a 150 mmol LiCl solution, either alone or together with tetracycline (33.5 mg/10 ml), ampicillin (33.5 mg/10 ml), or metronidazole (15 mg/10 ml). Urine was collected 1–5 hours after administration and blood samples were drawn after 1, 6, and 24 hours. All antibiotics caused a reduction in urinary lithium excretion but did not affect renal lithium clearance. Serum lithium levels were reduced by tetracycline and metronidazole 6 hours after administration but increased after 24 hours. Additional experiments including frequent mapping of serum lithium levels confirmed these findings. Tetracycline, also reduced renal sodium clearance and increased distal sodium reabsorption. Short‐term daily treatment during one week with tetracycline or metronidazole showed that these initial changes were only transient, since after treatment for one week no differences could be observed between antibiotic‐treated rats and control rats. The results indicate that antibiotics may cause a delay but no decrease of the gastrointestinal absorption of lithiim and that they do not affect renal lithium clearance. Signs of lithium intoxication during combined use of lithum and antibiotics are therefore probably not caused by a renal interaction mechanism affecting the renal lithium clearance.
Induction of Rat Hepatic Drug Metabolizing Enzymes by Substituted Urea Herbicides
Authors: Schoket Bernadette , Vincze István
Published: July 2010

Effects of eight structurally closely related substituted urea herbicides were investigated on the induction of cytochrome P‐450 dependent monooxygenase enzyme complex, as well as on two conjugating enzymes after short‐term treatment of rats. Liver microsomal cytochrome P‐450 content was induced approximately by 50%. Cytochrome P‐450 dependent monooxygenase activities showed a great variety depending on the substrate and on the herbicide. Two‐18‐fold induction was detected with 7‐ethoxycoumarin, while up to 8‐fold induction was measured with benzo(a)pyrene. Aldrin epoxidase activities were increased up to 3‐fold, and aminopyrine N‐demethylase activities were only slightly different from the control level. UDP‐glucuronyltransferase and glutathione S‐transferase activities were enhanced up to 2‐fold. The results indicate that chemical structure of the related substituted urea compounds, the number of halogen substituents on their phenyl group exert a strong influence on the induction of monooxygenases.
Interpretation and Application of World‐Wide Safety Data on Diltiazem
Authors: Quigley Mark A. , White Kenneth L. , McGraw Benjamin F.
Published: July 2010

Abstract: The safety of medicinal agents being introduced into the marketplace is of growing concern to consumers, health care providers, and regulatory agencies. Although there are ever increasing efforts to improve techniques for testing drugs, and for anticipating and confirming possible adverse effects, arrangements for monitoring and detecting adverse drug reactions are far from satisfactory. Some factors which need to be understood in order to appropriately interpret data include: maturation processes; pretesting affects, measuring instruments affects; selection bias; and the affects of differential experimental mortality. A safety profile has been presented for the calcium entry blocker diltiazem hydrochloride. Efforts were made to focus attention upon the source of safety information as it relates to the quality of the report. The data presented suggests that diltiazem hydrochloride has a low incidence of adverse experiences.
The Effect of Clodronate (Dichloromethylene Diphosphonate) on the Mineral Concentration of Dental Enamel and Bone of the Miniature Swine
Authors: Hyvönen P. M. , Hanhijärvi H. , Ahosilta K.
Published: July 2010

Abstract: Diphosphonates are compounds which prevent the crystallisation of calcium phosphates from solution. Our aim was to study the effects of clodronate (dicloromethylene diphosphonate), one of the diphosphonates, on the mineral cocentrations of dental enamel and bone. In a subchronic experiment the effects of this compound were investigated. The drug was administered orally in three doses (100, 300, 1000 mg/kg) per day to 32 Göttingen miniature swines for six months. From the acid etch biopsy of enamel the amount of dissolved hydroxyapatite and the concentrations of fluoride and magnesium were measured. The calcium, phosphorus, fluoride, magnesium, carbonate and citrate concentrations were determined from the cancellous bone sample. All values were calculated for dry bone. Calcium/phosphorus and calcium/magnesium ratios were calculated for both enamel and bone. In tooth enamel the magnesium concentration showed a significant dose dependent decrease and calcium/magnesium ratio a significant dose dependent rise. Calcium phosphorus/ratio exhibited a dose dependent increase in surface enamel. Bone fluoride concentration showed a highly significant and calcium/magnesium ratio a significant dose dependent rise. Clodronate seems to interfere with the remineralisation process of tooth enamel, through its effect on magnesium. Incorporation of the drug also appears to exhibit a marked action on the fluoride metabolism of bone. This may require attention in certain long term treatment situations with clodronate in high fluoride areas.