bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics of Clodronate after Single Intravenous, Intramuscular and Subcutaneous Injections in Rats
Authors: Laurén Leena , Österman Thua , Karhi Tero
Published: March 2009

Abstract: The pharmacokinetics of clodronate was studied in rats after single intravenous, intramuscular and subcutaneous doses of a mixture of unlabelled and 14C‐labelled disodium clodronate (25 mg/5 μCi/kg). The peak clodronate concentration in plasma was reached within 5 min., and the drug was eliminated with a half‐life of about 1.5 hr regardless of administration route. Bioavailabilities after intramuscular and subcutaneous administration were 105% and 89%, respectively. During the 72 hr collection period, the mean share of clodronate recovered from the urine was about 53% of the dose regardless of administration route. Most of the drug was excreted during the first 24 hr. The amount of clodronate in bone (femur) was 186 μg/g tissue at 2 hr after intravenous administration, 188 μg/g after intramuscular administration and 157 μg/g after subcutaneous administration. It is concluded that absorption of clodronate after intramuscular and subcutaneous administration is rapid and good, and that the concentrations of the drug in bone after 2 hr are about the same as after intravenous administration.
Influence of Pentamidine and Two New Trypanocidal Agents (DAPI, DIPI) on Liver Metabolism of Mice
Authors: Sippel H. , Steinmann U. , Estler C.‐J.
Published: March 2009

Abstract:The effects of equimolar doses (65.5 μmol/kg intraperitoneally) of three trypanocidal compounds, i.e. pentamidine, 6‐amidino‐2‐(amidinophenyl)indole (DAPI), and 6‐imidazolino‐2‐(imidazolinophenyl)indole (DIPI) on some parameters of liver carbohydrate, lipid and energy metabolism have been assessed in male NMRI mice. Most prominent effects were an initial increase of the blood glucose and fatty acid levels followed by long lasting increases of the hepatic triglyceride and glycogen contents which were accompanied by decreases of the liver pyruvate and lactate and ATP contents. These effects which can be interpreted as results of a transient lipolytic and glycogenolytic effect and a longer lasting inhibition of the energy yielding carbohydrate metabolism were most pronounced after DAPI and DIPI and less marked after pentamidine.
Inhibition of Dye Transfer in Rat Liver WB Cell Culture by Polychlorinated Biphenyls
Authors: Hemming Helena , Wärngård Lars , Ahlborg Ulf G.
Published: March 2009

Abstract: In the present investigation the scrape loading/dye transfer assay and microinjection technique are used in order to investigate inhibition of cell‐cell communication induced by different polychlorinated biphenyl (PCB) congeners. In these in vitro assays, inhibition of intercellular communication is directly measured as decreased transfer of a fluorescent dye (Lucifer Yellow CH) from donor cells loaded with the dye to surrounding recipient cells. The results show that substitution in the ortho position from the carbon bridge is essential and at least one chloro substitutent in ortho position is necessary for the ability to inhibit intercellular communication. The results also suggest that an increase in the number of ortho substituted chlorine atoms in the PCB molecule enhances the ability to inhibit intercellular communication. On the other hand, the total number of substitutions may not be crucial for the ability to inhibit intercellular communication. Our results suggest that PCB‐induced down‐regulation of intercellular communication is a result of a specific mechanism and not due to unspecific membrane pertubation.
TCDD Decreases Rapidly and Persistently Serum Melatonin Concentration Without Morphologically Affecting the Pineal Gland in TCDD‐Resistant Han/Wistar Rats
Authors: Linden Jere , Pohjanvirta Raimo , Rahko Timo , Tuomisto Jouko
Published: March 2009

Abstract: The highly toxic environmental contaminant, 2, 3, 7, 8‐tetrachlorodibenzo‐p‐dioxin (TCDD) was recently reported to decrease serum melatonin levels throughout the circadian cycle in the most TCDD‐susceptible strain of rat, Long‐Evans. To find out whether this effect is related to the mechanism of acute lethality of TCDD, serum melatonin levels were measured at the nocturnal peak phase in the most TCDD‐resistant rat strain variant, Han/Wistar rats, 6 hr to 28 days after TCDD exposure. The same dose as used in the previous study, 50 μg/kg, decreased serum melatonin levels to approximately half the control values by the first day after the treatment. Melatonin concentrations remained at this reduced level over the whole observation period. In an auxiliary experiment, Han/Wistar rats were dosed with 1000 μg/kg TCDD and killed on day 3. Neither light nor electron microscopic examination of their pineal glands revealed any alteration attributable to TCDD treatment. These findings might indicate that the reduction of serum melatonin levels in the rat by TCDD is not related to its lethal effect and is not due to a direct damage of the pineal gland.
Characterization of the Enhanced Responsiveness to Postingestive Satiety Signals in 2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin (TCDD)‐Treated Han / Wistar Rats
Authors: Pohjanvirta Raimo , Unkila Mikko , Tuomisto Jouko
Published: March 2009

Abstract: Previous studies have shown that under free‐feeding conditions, TCDD‐treated Han/Wistar (H/W) rats consume less sucrose solution but ingest more saccharin solution than their controls thus implying hyperresponsiveness to postingestive satiety signals. In this study, nutrient preloads were employed to further elucidate this phenomenon. Male H/W rats were given a single high but usually non‐lethal intraperitoneal dose (1000 g̈/kg) of TCDD. Feed intake was stimulated by 24 hr feed deprivation at various time points after TCDD exposure. When TCDD‐dosed rats were allowed to drink either a 20% sucrose or a 0.25% saccharin solution and then given access to feed, those that had had sucrose ate only about 50% of the amount consumed by the saccharin group. Although the preloads were similar in control rats, no such difference in subsequent feeding occurred. The sucrose solution also produced a longer‐lasting suppression of feed intake in TCDD‐treated compared with control rats when infused directly into the stomach. By contrast, TCDD‐treated H/W rats failed to exhibit an augmented satiety response to parenterally applied glucose independent of testing time. Oral corn oil reduced feed intake in both control and TCDD‐exposed rats, but the inhibition was slightly larger in TCDD‐treated animals. TCDD did not markedly affect the responsiveness of H/W rats to the suppression of feeding by CCK‐8 or bombesin. It is concluded that gastrointestinal factors appear critical to the exaggerated response of TCDD‐treated H/W rats to nutrient energy.
Swedish Dioxin Survey: Evaluation of the H‐4‐II E Bioassay for Screening Environmental Samples for Dioxin‐Like Enzyme Induction
Authors: Hanberg Annika , Stahlberg Margareta , Georgellis Antonis , de Wit Cynthia , Ahlborg Ulf G.
Published: March 2009

Abstract: The H‐4‐II E enzyme induction bioassay was used for testing both pure reference substances and extracts of wildlife samples. Polychlorinated naphthalenes were found to be as active as enzyme inducers as certain coplanar polychlorinated biphenyls (PCBs). Also a mixture of polybrominated diphenyl ethers (Bromkal® 70‐5DE) was shown to induce enzyme activity. In extracts of herring, containing polychlorinated dibenzo‐p‐dioxins (PCDDs) and dibenzofurans (PCDFs), bioassay and chemically derived TCDD‐equivalents (TEQs) were nearly identical. When extracts containing other types of dioxin‐like compounds as well were tested, the bioassay TEQs for most of them agreed well with chemical TEQs calculated for PCDDs, PCDFs and non‐ortho PCBs. However, for ringed seal and whitefish, TEQs obtained from the bioassay were higher than those from the chemical analysis. Our results indicate that this bioassay is an excellent complement to chemical residue analysis and a useful tool in understanding the complex interactions of halogenated hydrocarbons. For risk assessment, such results should, however, be used most carefully as they are measured in vitro.
Lithium Increases the α1‐Adrenoceptor Mediated Inotropic Effect in Rat Heart
Authors: Skomedal T. , Schiander I. G. , Husøy E. A. , Tveiten A. , Osnes J. B.
Published: March 2009

Abstract:The intracellular mechanisms activated by stimulation of myocardial α1‐adrenoceptors are not known. As in several other tissues, however, activation of α1‐adrenoceptors in heart has been related to breakdown of phosphoinositides resulting in production of putative intracellular messengers: different inositol phosphates and diacylglycerol. Lithium has been shown to inhibit enzymes hydrolyzing inositol phosphates. In the present paper we report studies on the effect of lithium upon the α1‐adrenoceptor mediated inotropic response elicited in electrically driven rat papillary muscles. While there was no shift of the horizontal positioning of the dose‐response curve to α1‐adrenergic stimulation in the presence of lithium, the α1‐adrenoceptor mediated inotropic effect was increased in a concentration dependent manner (0.25 to 3.0 mmol/l lithium). For comparison, the effect of lithium upon the β‐adrenoceptor mediated inotropic response was also studied. At 3.0 mmol/l lithium, the horizontal position of the dose‐response curve to β‐adrenoceptor stimulation was shifted significantly to the right (to higher agonist concentrations) and the maximal β‐adrenoceptor mediated inotropic response was slightly although not significantly reduced. Thus the augmenting effect of lithium upon the α1‐adrenoceptor mediated response was specific for this receptor type. Although the effect of lithium may be complex, the data are compatible with the hypothesis that the inositol phosphates may be of functional importance during stimulation of myocardial α1‐adrenoceptors.
Effects of Phenoxyacetic Acid Herbicides on Chicken Embryo Liver Drug Metabolizing Enzymes
Authors: Santagostino A. , Leone M. P. , Maci R. , Casale A. , Marabini L.
Published: March 2009

Abstract:Chick embryos were treated on day 0 of incubation with two phenoxy herbicides, 2‐methyl‐4‐chlorophenoxyacetic acid (MCPA) (0.4, 2 mg/egg) and 2,4‐dichlorophenoxyacetic acid (2, 4‐D) (1, 2, 4 mg/egg). Both herbicides seemed to exert toxic effects mainly on the liver of 19‐day‐old embryos. Specific histological analysis indicated biliary stasis. Ethoxycoumarin O‐deethylase was depressed by MCPA but raised by 2, 4‐D. Other hepatic monooxygenase activities were unaffected by the herbicides and no significant changes were found in cytochromes. The higher dose of MCPA increased NADPH‐cytocrome P450reductase. 2,4‐D treatment increased by activity of glutathione‐S‐transferases in the hepatic post‐microsomal fraction while MCPA increased them at the lower dose and significantly reduced them at the higher. The phenoxyacetic herbicides appear thus to have some effects on hepatic drug metabolizing enzymes of the chick embryo which cannot be easily interpreted. Biliary retention, produced in particular by MCPA, could be partly responsible for these effects.
Dithiocarbamates of Improved Efficacy for the Mobilization of Retained Cadmium from Renal and Hepatic Deposits
Authors: Jones Mark M. , Singh Pramod K. , Jones Shirley G. , Holscher Myron A.
Published: March 2009

Abstract:The preparation and properties of two novel cadmium‐mobilizing dithiocarbamates namely, sodiumN‐(4‐methylbenzyl)‐and sodiumN‐(4‐methoxybenzyl)‐4‐O‐(β‐D‐galactopyranosyl)‐D‐glucamine‐N‐carbodithioates derived from α‐lactose and substituted benzylamines are described. These compounds are more effective than previously prepared compounds of this type for the mobilization of cadmium from its aged deposits in both the liver and the kidneys. An examination of the structural features of the more effective compounds for the mobilization of cadmium from its aged deposits reveals that the combination of a high molecular weight with a suitable amphipathic structure in which the polar and non‐polar groups are in an appropriate balance are key features. A histopathological evaluation of the animals from which cadmium is removed by these compounds indicates no variations from the normal for the kidney and no evidence of hepatic damage resulting from the removal of the cadnium. On the basis of the trends observed in cadmium mobilizing efficacy, there are grounds for suspecting that agents which are significantly more effective than any prepared so far, should also be accessible.
Suicidal Inactivation of Human Cytochrome P‐450 by Carbon Tetrachloride and Halothanein Vitro
Authors: Manno M. , Ferrara R. , Cazzaro S. , Rigotti P. , Ancona E.
Published: March 2009

Abstract:A significant loss of human cytochrome P‐450 was observed during the anaerobic incubation of NADPH‐reduced human liver microsomes obtained from surgical samples, in presence of carbon tetrachloride or halothane. In order to prevent any interference in the classical spectrum of cytochrome P‐450 with CO, the method of Johannesen & DePierre (1978) was modified to obtain cytochrome P‐450 determination. The enzyme inactivation reaction showed pseudo‐first order kinetics and was accompanied by destruction of the haem tetrapyrrolic structure, as indicated by a significant loss of its porphyrin fluorescence. Values of about 200 and 700 were calculated for the partition ratio between metabolic turnover of the substrate and enzyme inactivation during reductive incubation of one of these microsomal preparations with limiting concentrations of CCl4and halothane, respectively. The results indicate that human liver cytochrome P‐450 can be inactivated reductivelyin vitroby CCl4and halothane reactive metabolites and suggest that a suicide type of mechanism, similar to that which was recently demonstrated to occur, for both substrates, with rat liver microsomes (Mannoet al.1988a & 1991), may also be involved in the inactivation of the human enzyme(s).
Effects of Noradrenaline and Prostaglandin F2αon Angiotensin‐Induced Contraction and Tachyphylaxis in Rat Aortic Rings
Authors: Sim M. K. , Kuttan S. C.
Published: March 2009

Abstract:The aim of this study was to examine the effects of noradrenaline (NA) and prostaglandin F2α(PGF2α) on angiotensin II (AII)‐induced contraction and tachyphylaxis in aortic rings of the rat. Neither NA (10–9M) nor PGF2α(10–7M) had significant effect on the response of the rings to the spasmogenic concentrations (10–10to 10–7M) of AII, but lowered significantly the threshold response of the aortic rings to AII (from 10–9to 10–12M). In rings that were tachyphylatic to AII, both NA and PGF2αattenuated significantly the tachyphylaxis of the rings to AII at the concentrations of 10–10and 10–7of the octapeptide; and also lowered the threshold of the tachyphylatic rings to AII (from 10–9to 10–11M for NA, and from 10–9to 10–10M for PGF2α). The specific properties of noradrenaline and PGF2αwere not shared by the non‐specific potassium chloride. Because the lowering of threshold and attenuation of tachyphylaxis occurred at the physiological levels of AII and NA, it is possible that thein vivoactions of AII are under constant modulation by circulating and localised (higher than circulating) levels (e.g. of PGF2α) of spasmogens. The results also call into question the physiological significance of angiotensin tachyphylaxis and may suggest that it is only anin vitrophenomenon occurring in the absence of endogeneous spasmogens.
Adipose Tissue Distribution and Chemical Structure of Basic Lipophilic Drugs: Desipramine, N‐Acetyl Desipramine, and Haloperidol
Authors: Moor M. J. , Steiner S. H. , Jachertz G. , Bickel M. H.
Published: March 2009

Abstract:Single‐dose intravenous injections of desipramine to rats resulted in a distribution pattern typical of basic lipophilic drugs, i.e., highest concentrations in lung and lowest in adipose tissue and plasma. In contrast, after N‐acetyldesipramine, a non‐basic analogue of desipramine with comparable lipophilicity, concentrations of this drug in adipose tissue were much higher than in lean tissue or plasma as a result of redistribution into the former and rapid disappearance from the latter tissue. N‐Acetyldesipramine had much lower plasma and tissue half‐lives than desipramine, but at the same time a much higher adipose/plasma concentration ratio and adipose storage index. Chronic administration of the basic lipophilic drug, haloperidol, to rats in their diet over 21 days resulted in a steady‐state distribution pattern with highest concentrations in lung and lowest concentrations without accumulation in adipose tissue. This study provides additional evidence for the influence of basic groups on the distribution of lipophilic drugs. Thus, basic lipophilic drugs do not undergo redistribution into adipose tissues, possibly because of a competition by stronger binding to lean tissue as a result of lysosomotropism.
Antinociceptive Effects and Central Nervous System Depression Caused by Oxycodone and Morphine in Rats
Authors: Pöyhiä Reino , Kalso Eija A.
Published: March 2009

Abstract:Antinociception and central nervous system depression (CNSD) caused by intraperitoneal, intrathecal and subcutaneous administration of oxycodone or morphine were studied in a randomized and blind, saline controlled study in rats. Antinociception was assessed with the tail‐flick and hot plate tests. CNSD was assessed by testing the corneal, placing and righting reflexes and with a 4‐point catalepsy score. Intraperitoneally and subcutaneously administered oxycodone and morphine were given in doses of 2.5–10 and 5–20 mg kg–1respectively. The intrathecal doses were 12.5 μg and 100 μg of oxycodone and 6.25 μg and 50 μg of morphine. In both nociceptive tests subcutaneously and intraperitoneally administered oxycodone was 2–4 times more potent than morphine, while intrathecal morphine was over 14 times more potent. CNSD was more profound with oxycodone than with morphine after intraperitoneal and subcutaneous administration, but was not observed after intratechal administration of either drug. Differences in opioid receptor affinities, liposolubilities and metabolism are discussed as possible explanations.
Interactions and Comparative Effects of Zopiclone, Diazepam and Lorazepam on Psychomotor Performance and on Elimination Pharmacokinetics in Healthy Volunteers*
Authors: Saano V. , Hansen P. P. , Paronen P.
Published: March 2009

Abstract: A randomised, placebo‐controlled, double blind single‐dose cross‐over study was arranged to investigate possible interactions between zopiclone (7.5 mg) and two widely used benzodiazepine (BZD) anxiolytics diazepam (5 mg) and lorazepam (1 mg) during the elimination phase of drugs. Psychomotor performance was tested before and 1, 6, 8, 12 and 24 hr after the drug administration. Simultaneously, blood samples were drawn for determination of plasma drug concentrations. The elimination of each compound was not altered by coadministration of other drugs. As expected, one hour after drug ingestion, psychomotor performance was impaired. The coadministration of drugs increased the effect. During the elimination phase, 6 and 8 hr after the drug intake, only zopiclone and lorazepam in combination slightly impaired performance as compared with the pretreatment levels, but there was no difference as compared with placebo. Adverse events after active treatments were not significantly different from those after placebo. At the recommended dose of 7.5 mg, zopiclone does not alter the elimination pharmacokinetics of the BZD anxiolytics diazepam (5 mg) and lorazepam (1 mg), and neither is the elimination of zopiclone affected by these BZDs. Due to the rapid elimination of zopiclone, the increase in sedation seen after concurrent administration with BZDs is of short duration.
Comparative Study of Nitroimidazoles on the Bioelectric Properties of Frog Skin as a Membrane Model
Authors: Rybczynska Maria , Simon Marek , Breborowicz Halina
Published: March 2009

Abstract: The effects of misonidazole (MISO) and two other nitroimidazoles (5‐NO2 and 4, 5‐NO2) on the bioelectric parameters of ion transport (potential difference and short circuit current) across frog skin as a membrane model, were studied in vitro. The nitroimidazoles investigated caused structure dependent effects on the sodium transport function of the membrane. MISO induced a biphasic action following administration on the external side of the membrane: after an initial enhancement, the potential difference and short circuit current signals both decreased. The other imidazole derivatives, 5‐NO2 and 4, 5‐NO2, showed only one phase, whether administered on the external or internal membrane surface. All the nitroimidazoles investigated decreased sodium transport after internal or external surface administration. It was found that the 4, 5‐NO2 imidazole derivative irreversibly decreased the bioelectric membrane parameters.
Accumulation of Aluminium in Rat Liver: Association with Constituents of the Cytosol
Authors: Van Der Voet Gijsbert B. , Brandsma Annelies E. , Heijink Elisabeth , De Wolff Frederik A.
Published: March 2009

Abstract: Aluminium (A1) accumulation occurs in the liver of renal patients and in patients on parenteral nutrition. Human hepatotoxicity is not proven. The role of the liver in storage and biotransformation of A1 and in development of osteo‐ and neurotoxicity is not clarified as yet. The aim of the present investigation was to study the storage of A1 in total liver and in subcellular liver fractions, and its association with soluble cytosolic molecular species. Therefore, rats were loaded with A1 prior to liver fractionation by ultracentrifugation, and equilibrium gel filtration chromatography of the cytosol, using a previously described method for A1 speciation in serum. A1 accumulated dose‐dependently in liver and subcellular liver fractions, the lowest levels occurring in the cytosol. A dose‐dependent elevation of A1 in the blood was also observed. Gelfiltration of the cytosol indicated that A1 was associated with a low molecular weight form which was not a citrate complex, and a high molecular weight form, which was larger than transferrin. No induction of and association with metallothionein occurred.
Simplified Test for Determination of Drug‐Oxidizing Capacity in Rats with Chemical‐Induced Liver Injury Using Caffeine and Trimethadione as Model Drugs
Authors: Tanaka Einosuke , Ishikawa Akio , Misawa Shogo
Published: March 2009

Abstract:We examined the possibility of predicting the extent of hepatic drug‐oxidizing capacity by determination of caffeine, trimethadione and their metabolites in three groups of rats with chemically induced liver injuries. Trimethadione (4 mg/kg) and caffeine (10 mg/kg) were simultaneously administered as two probe drugs. In rats with chemically induced liver injuries pretreated with carbon tetrachloride (CCl4: 0.25 ml/kg), α‐naphthylisothiocyanate (ANIT: 40 mg/kg), or D‐galactosamine (GalN: 400 mg/kg), the half‐life (t1/2) of caffeine and trimethadione was significantly (P < 0.01) prolonged compared to those of control groups total body clearance as dramatically reduced (P < 0.01), whereas apparent volumes of distribution (Vds) were increased in ANIT and GalN groups. In rats with liver damage the production of three metabolites (theobromine, paraxanthine and theophylline) of caffeine as well as the only metabolite (dimethadione) of trimethadione after oral administration of both drugs were significantly decreased compared to those of controls. In rats with liver injuries, total body clearance of caffeine and trimethadione showed a strong correlations (r = 0.99, P < 0.01); also total body clearance of caffeine correlated well with the ratio of dimethadione/trimethadione after 1, 2, and 4 hr of trimethadione administration (r = 0.93, P < 0.01; r = 0.97, P < 0.01 and r = 0.97, P < 0.01 respectively). Besides, total body clearance of caffeine also correlated well (coefficients ranging from 0.74 to 0.96; P < 0.01) with the ratio of theobromine/ caffeine, paraxanthine/caffeine and theophylline/caffeine after 1, 2 and 4 hr) of caffeine administration. These findings indicate that the hepatic drug‐oxidizing capacity can be evaluated by measuring the plasma concentration ratios of caffeine or trimethadione to their metabolites using single blood sampling within a short time (1 or 2 hr) after administration of caffeine or trimethadione to rats with chemically induced liver injuries.
Effect of Organic Solvents on Nervous Cell Membrane as Measured by Changes in the (Ca2+/Mg2+) ATPase Activity and Fluidity of Synaptosomal Membrane
Authors: Edelfors Sven , Ravn‐Jonsen Andree
Published: March 2009

Abstract: The effect of various solvents on the central nervous system was studied by using rat brain synaptosomal membranes as an in vitro model. The activity of (Ca2+/Mg2+) ATPase and the membrane fluidity was determined. The alteration of the ATPase activity depended on the physio‐chemical characteristics of the solvent in question. Incubation with aliphatic alkanes caused a stimulation of the ATPase activity whereas mixed hydrocarbons as kerosene, white spirit and gasoline inhibited the enzyme. Incubation with chlorinated hydrocarbons caused a biphasic response dependent on the concentration. Oxygen‐containing hydrocarbons exhibited various effects as found after incubation with hydrocarbons. The different effects of the solvents on the ATPase activity suggest that the lipophilicity of the solvents is one of more parameters affecting the membrane. Furthermore, the biphasic response following the incubation with chlorinated hydrocarbons indicates that more mechanisms are involved in the enzyme effect. The membrane fluidity is increased with higher concentrations of the solvents. From the results it is concluded that the ATPase activity depends not only on the membrane fluidity and volume, but also on the hydrophilic vicinity of the enzyme molecule.
The Role of Mg2+on the Formation of the Ternary Complex between Agonist, β‐Adrenoceptor, and Gs‐Protein and an Interpretation of High and Low Affinity Binding of β‐Adrenoceptor Agonists
Authors: Johansson Lars‐Håkan , Persson Henry , Rosengren Evald
Published: March 2009

Abstract:In the absence of GTP or its analogues, the β‐adrenoceptor agonist (H), the receptor (R) and the stimulatory guanine nucleotide‐binding regulatory protein (Gs‐protein) form a slowly dissociable complex (HRGSGDP). It is presumed that the agonist in this ternary complex is bound to the receptor with high affinity while its binding to the receptor in the HR‐complex is of low affinity. We have studied the effect of Mg2+on the formation of these two complexes by the displacement of (‐)‐[3H]CGP‐12177 with (‐)‐isoprenaline in cell membranes prepared from guinea‐pig lung parenchyma. In the absence of Mg2+, only monophasic displacement curves were obtained with a dissociation constant not differing from that obtained in the presence of Gpp(NH)p and Mg2+. In the presence of Mg2+and absence of Gpp(NH)p, a shallow binding curve was obtained that fitted a two site model best. One of the dissociation constants agreed well with that obtained in the presence of Gpp(NH)p and Mg2+but the other one was 27 times smaller. It was concluded that Mg2+is necessary for the coupling between the HR‐complex and the Gs‐protein. The two dissociation constants obtained in the absence of Gpp(NH)p represent the dissociation constants of the HR‐ and HRGSGDP‐complexes and may correspond to those named KLand KHin the literature. According to our study, there may be no difference in affinity between the agonist and receptor in the HR‐ and HRGSGDP‐complexes. The two dissociation constants obtained in the absence of GTP or its analogues refer to two consecutive reactions.
Equipotent Allosteric Effect of W84 on [3H]NMS‐Binding to Cardiac Muscarinic Receptors from Guinea‐Pig, Rat, and Pig*,**
Authors: Mohr Klaus , Staschen Carl‐Michael , Ziegenhagen Manfred
Published: March 2009

Abstract:W84 (hexamethylene‐bis‐[dimethyl‐(phthalimidopropyl)‐ammonium bromide]) is an experimental antidote against organophosphorus poisoning and has been found to affect muscarinic cholinoceptors allosterically. The attempt was made to test whether the W84‐action on muscarinic cholinoceptors depends on the species. For this purpose, the effect of W84 on the binding of [3H]N‐methylscopolamine ([3H]NMS) was investigated in membrane‐suspensions from the hearts of guinea pigs, rats, and pigs in 3mM MgHPO4, 50 mM Tris, pH 7.3, at 23°. W84 inhibited [3H]NMS‐binding in the three membrane suspensions with similar potency (half‐inhibitory concentration IC50: 2‐5μM). To evaluate the allosteric activity of W84, its effect on the dissociation of [3H]NMS was determined. At 3μM, W84 diminished the rate of [3H]NMS‐dissociation to about 20% of the control in the three suspensions. At 3μM of W84, [3H]NMS‐dissociation was almost prevented. In conclusion, W84 acted equally on the cardiac cholinoceptors of guinea pigs, rats, and pigs, respectively. It can be anticipated that M2‐cholinoceptors of other species would likewise be affected by W84.
Effects of Amiloride on Distal Renal Tubule Sodium and Calcium Absorption: Dependence on Luminal pH
Authors: Mori Y. , Machida T. , Miyakawa S. , Bomsztyk K.
Published: March 2009

Abstract:The goal of our study was to examine the effects of amiloride on distal renal tubule calcium and sodium absorption at low and high luminal pH.In vivomicroperfusion of distal convoluted tubules were performed on rats. Total Ca and Na concentrations in perfusion and collected fluids were measured by atomic absorption spectrometry. When tubules were perfused with low pH perfusate (pH = 5.6), net calcium absorption (JCa) averaged 5.4 pmol/min. With high pH perfusate (pH = 7.1), JCawas significantly higher averaging 8.9 pmol/min. (P < 0.01). In contrast, net sodium absorption (JNa) was not affected by luminal pH (231 pmol/min. versus 237 pmol/min.). At low luminal pH, 10–4M amiloride analogue (5‐N‐methyl‐N‐isobutyl amiloride) (MIA) inhibited sodium absorption but stimulated calcium absorption. At high luminal pH MIA still inhibited Na absorption but it had no effect on calcium absorption. Thus, the natriuretic effect of amiloride appears to be independent of luminal pH, while the amiloride‐stimulated distal calcium absorption is observed at low but not at high luminal pH.
Pharmacology of Vigabatrin
Authors: Sabers Anne , Gram Lennart
Published: March 2009

Abstract: Vigabatrin (gamma‐vinyl GABA) is a relatively new antiepileptic drug. Vigabatrin increases the concentration of gamma‐aminobutyric acid (GABA) in the brain by inhibiting the major GABA metabolizing enzyme, GABA transaminase. Controlled clinical trials have demonstrated an excellent antiepileptic effect of vigabatrin, especially in the treatment of partial epilepsies. Long‐term evaluations have shown no signs of tolerance development. Vigabatrin decreases the plasma concentration of phenytoin during concomitant therapy, the only drug with which an interaction seems to occur. In general, vigabatrin is well tolerated. Psychotic reactions occur in 3–6% of patients. Other frequent side effects are sedation and weight increase. Chronic vigabatrin intoxication in animals caused development of intramyelinic oedema, appearing as microvacuoles in brain white matter. No microvacuolation has been observed in humans, even after long‐term treatment. Vigabatrin seems a very valuable new antiepileptic drug.
Localization of Gastrointestinal Deposition of Mercuric Chloride Studied in Vivo
Authors: Nielsen J. B. , Andersen H. L. , Serensen J. A. , Andersen O.
Published: March 2009

Abstract: During the last 5 years, the site of gastrointestinal absorption of inorganic mercury has been attempted identified mainly by experiments using perfused intestinal segments in vitro or in situ. The present investigation will discuss the localization of the absorption site for mercuric chloride based on a completely undisturbed in vivo experimental model in mice. As the mice were allowed to eat their normal diet during the experimental period, the present results would independently add to existing knowledge on intestinal absorption sites for inorganic mercury. The mice were given 203Hg labelled mercuric chloride orally, either through stomach tube or in the drinking water, and were killed after various time intervals. Mercury was localized and quantified in various segments of the gastrointestinal tract by gamma‐counting. Time course analysis of the segmental deposition of mercury demonstrated that the deposition mainly takes place in the proximal jejunum and suggested that a larger part of the jejunum than previously reported is involved in absorption of mercury. Using this in vivo model, tetraethylthiuram disulfide was demonstrated to increase the intestinal deposition and absorption without changing the site of deposition.
Evidence for a Hazardous Interaction between Ethanol and the Insecticide Endosulf an in Rats
Authors: Paul Vanaja , Balasubramaniam E. , Muthu P. , Krishnamoorthy M. S.
Published: March 2009

Abstract: Protein supplemented diet was protective against the deleterious action of endosulfan on body growth and liver. Hepatomegaly and a reduction of body weight produced concurrently by endosulfan and ethanol were greater in male rats, suggesting that males are more susceptible than female rats to the metabolic stress caused by their interaction. Chronic endosulfan exposure resulted in a prolongation of ethanol sleeping time in female and not in male rats. This finding suggests failure of female rats to metabolize ethanol readily on account of their greater susceptibility than male rats to the hepatotoxic action of endosulfan.
Effects of Antioxidants on Oxygen Toxicityin Vivoand Lipid Peroxidationin Vitro
Authors: Lin Yiguang , Jamieson Dana
Published: March 2009

Abstract:Convulsions and pulmonary damage result when animals are exposed to hyperbaric oxygen at pressures above about 300 kPa. Several hydroxyl radical scavengers (namely dimethylsulphoxide, dimethylthiourea and mannitol), the iron chelator desferoxamine and the lipid antioxidant butylated hydroxytoluene were tested for possible protection against such hyperbaric oxygen toxicity. Dimethylthiourea and dimethylsulphoxide prolonged the latency to the first convulsion, but, surprisingly, dimethylthiourea very significantly increased pulmonary damage at both pressures used (515 and 585 kPa). Desferoxamine also slightly increased lung damage at 585 kPa. Other antioxidants did not alter neurotoxicity or pulmonary toxicity induced by hyperbaric oxygen at 515 or 585 kPa. The antioxidants were also tested for their ability to inhibit lipid peroxidation (TBARS formation)in vitro. Desferoxamine (5 and 50 μM), and butylated hydroxytoluene (0.1 mM and 1 mM) greatly inhibited TBARS formation in brain and lung homogenates incubated at 37°. None of the hydroxyl radical scavengers affected TBARS levels in homogenates. There was no correlation between in vitro inhibition of lipid peroxidation andin vivoprotection against oxygen toxicity.
Aluminium‐Adjuvanted Vaccines Transiently Increase Aluminium Levels in Murine Brain Tissue
Authors: Redhead K. , Quinlan G. J. , Das R. G. , Gutteridge J. M. C.
Published: March 2009

Abstract: Aluminium is widely used as an adjuvant in human vaccines, and children can often receive upto 3.75 mg of parenteral aluminium during the first six months of life. We show that intraperitoneal injection of aluminium adsorbed vaccines into mice causes a transient rise in brain tissue aluminium levels peaking around the second and third day after injection. This rise is not seen in the saline control group of animals or with vaccine not containing aluminium. It is likely that aluminium is transported to the brain by the iron‐binding protein transferrin and enters the brain via specific transferrin receptors.
Changes in Rat Striatum Catecholamine during Hypoxia with Reference to Protective Effects of Flunarizine
Authors: Yamazaki Mitsuaki , Masuda Toru , Ito Yusuke , Kuze Shougo , Momose Yasunori
Published: March 2009

Abstract: We investigated the changes in dopamine, homovanillic acid, 3, 4‐dihydroxyphenylacetic acid, and norepinephrine content in striatum of rats ventilated with 5% oxygen in nitrogen gas. We also examined the effects of flunarizine, a calcium channel blocker, on these catecholamine levels. During 10–20 min. of hypoxia, the dopamine content gradually increased and the 3, 4‐dihydroxyphenylacetic acid and norepinephrine levels decreased, while the concentration of homovanillic acid remained unchanged. The concentrations of these substances subsequently returned to control values after 4 hr of room air breathing. In animals pretreated with intravenous flunarizine injection, there was a slight increase in dopamine, with no appreciable change in homovanillic acid or 3, 4‐dihydroxyphenylacetic acid content during 10–20 min. of hypoxia. The decrease in norepinephrine which occurred during 10–20 min. of hypoxia was identical between non‐treated and flunarizine‐treated animals. Catecholamine levels subsequently returned to control values after 4 hr of room air breathing. These results suggest that flunarizine minimizes the alterations in striatal catecholamine contents during hypoxic ventilation.
Dental Amalgam and Mercury
Authors: Jokstad Asbjørn , Thomassen Yngvar , Bye Erik , Clench‐Aas Jocelyne , Aaseth Jan
Published: March 2009

Abstract: The mercury concentrations in blood (HgB) and urine (HgU) samples, and in exhaled air (HgAir) were measured in 147 individuals from an urban Norwegian population, using cold vapour atomic absorption spectrometry. The study aimed to estimate the mercury exposure from the dental restorations, by correlating the data to the presence of amalgam restorations. Mean values were HgB=24.8 nmol/1, HgU=17.5 nmol/1 and HgAir=0.8 μg/m3. HgU correlated with HgAir, and both HgU and HgAir with the number of amalgam restorations, amalgam restored surfaces and amalgam restored occlusal surfaces. HgB showed poor correlation to HgU and HgAir and the presence of amalgam restorations. A differentiation of the mercury absorption due to exposure from dental amalgams and from the dietary intake, necessitates measurements of both organic and inorganic mercury in the plasma, and in the erythrocytes. The results suggest that individuals with many amalgam restorations, i.e., more than 36 restored surfaces, absorb 10–12 μg Hg/day.
The Pharmacological Profile of (–)Deprenyl (Selegiline) and its Relevance for Humans: A Personal View
Authors: Knoll J.
Published: March 2009

Abstract: Deprenyl (selegiline, jumex, eldepryl, movergan) which is closely related to phenylethylamine (PEA) is a drug with a unique pharmacological spectrum. Single dose effects: (a) It is a highly potent and selective inhibitor of B‐type monoamine oxidase (MAO), (b) In contrast to other MAO inhibitors it inhibits the noradrenaline releasing effect of tyramine, is therefore free of the ‘cheese effect’. Multiple dose effects unrelated to MAO inhibition: (a) It enhances superoxide dismutase and catalase activity in the striatum, (b) It facilitates the activity of the nigrostriatal dopaminergic neurones, (c) It prevents age‐related morphological changes in the neurocytes of the substantia nigra. Consequences of multiple dose effects: Compared to salt solution‐treated rats, male rats maintained on (–)deprenyl loose their capacity to ejaculate later on; retain for longer their learning ability; and live longer. Freshly diagnosed Parkinson's patients maintained on (–)deprenyl, require levodopa later than their placebo‐treated peers. Patients treated with levodopa plus (–)deprenyl live longer than those on levodopa alone. Chronic treatment with (–)deprenyl improves the performance of patients with Alzheimer's disease.
Failure of Epinephrine to Induce Severe Cardiac Arrhythmia in Rats with Ventricular Hypertrophy Secondary to Aortic Pressure Overload
Authors: Lessard Yvon , Mabo Philippe , Daubert Jean‐Claude , Kerbaol Michel
Published: March 2009

Abstract: The arrhythmogenic action of epinephrine was studied in 3 groups of rats: 10 rats with mild constriction of the abdominal aorta (group H1), 10 rats with severe constriction (group H2), 10 sham‐operated age‐matched rats (group C). Blood pressure and ECG were recorded before, during and after 5 min. perfusion of increasing doses of epinephrine (1, 5, 10 and 25 μ·g‐kg–1 · min.–1). Ventricular arrhythmia was evaluated from the ECG using a modified Lown's grading system. The ventricular hypertrophy index was calculated from the heart/body weight ratio (mg/g). The mean arterial blood pressure was significantly higher in groups H1 and H2 than in the control group. The ventricular hypertrophy was significant in group H2, but not in group H1. There was no significant difference between the amplitudes of the epinephrine‐induced hypertensive responses in the 3 groups but the extent of arrhythmia was significantly lower in the animals with high hypertrophy index.
Cadmium Mobilization in Vivo by Intraperitoneal or Oral Administration of Monoalkyl Esters of meso–2, 3–Dmercaptosuccinic Acid in the Mouse
Authors: Jones Mark M. , Singh Pramod K. , Gale Glen R. , Smith Alayne B. , Atkins Loretta M.
Published: March 2009

Abstract: The relative activities of a series of nine monoalkyl esters of meso‐2, 3–dimercaptosuccinic acid have been examined as agents for the mobilization of cadmium from mice one week after intraperitoneal administration of cadmium chloride. Eight of these are newly synthetized; all are of the type ROOCCH(SH)CH(SH)COOH, were R=Me, MMDMS; R = C2H5, MEDMS; R = (CH2)2CH3, Mn‐PDMS; R = CHMe2) Mi‐PDMS; R = (CH2)3CH3, Mn‐BDMS; R = CH2CHMe2, Mi‐BDMS; R = (CH2)4CH3, Mn‐ADMS; R=(CH2)2CHMe2, Mi‐ADMS; and R = (CH2)5CH3, Mn‐HDMS. All are soluble in dilute sodium bicarbonate solutions and can be administered as aqueous solutions. Cadmium mobilization data were collected on each compound using mice previously loaded with cadmium; the monoesters were administered at a level of 0.40 mmol/kg intraperitoneally daily for five days. Data on whole body cadmium mobilization indicated that the monoester with the isoamyl group was the most effective under the conditions used. The relative whole body cadmium mobilization increased with the number of carbon atoms in the alkyl group of the monoester up to C5 and then decreased for the C6 compound. Cadmium removal from the kidneys and liver was also measured. It was found that the monoisoamyl ester was the most effective in removing cadmium from both the liver and the kidneys. The monoisoamyl ester also proved to be very effective in mobilizing cadmium from both the liver and the kidneys when given orally. This is the first compound which is reported capable of mobilizing cadmium in vivo from aged deposits after oral administration.
Cationic and Secretory Effects of Glimepiride and Glibenclamide in Perifused Rat Islets
Authors: Lebrun Philippe , Malaisse Willy J.
Published: March 2009

Abstract:The effects of glimepiride and glibenclamide upon86Rb outflow,45Ca outflow and insulin release were examined in rat islets perifused at low (zero to 2.8 mM) or close‐to‐normal (8.3 mM) D‐glucose concentrations. At the low hexose concentrations, a marked and not reversible decrease in86Rb outflow contrasted with a rapid and reversible increase in45Ca outflow. The latter increase was abolished in the absence of extracellular Ca2+, and was not associated with any pronounced stimulation of insulin release. Inversely, in the presence of 8.3 mM D‐glucose, a comparable increase in45Ca efflux now coincided with an increase in86Rb efflux and a marked and not reversible stimulation of insulin release. Whether in terms of the time course or glucose dependency of the cationic and secretory responses, a coupled increase in both40Ca inflow and45Ca outflow thus coincided with either negative or positive changes in86Rb outflow and either minimal or marked changes in insulin output. Such dissociated behaviours suggest that the insulinotropic action of hypoglycemic sulfonylureas is not necessarily attributable solely to a primary decrease in K+conductance.
Inhibition of Ornithine Aminotransferase by 5‐Fluoromethylornithine: Protection Against Acute Thioacetamide Intoxication by Elevated Tissue Ornithine Levels
Authors: Seiler Nikolaus , Sarhan Shakir , Knödgen Bernd
Published: March 2009

Abstract: 5‐Fluoromethylornithine (5FMOrn) is a selective inactivator of ornithine aminotransferase. Its administration causes a dramatic increase of ornithine concentrations in all tissues. Treatment of mice with 20 mg.kg–1 5FMOrn shortly before or after a lethal dose (600 mg.kg–1, intraperitoneally) of thioacetamide (TAA), followed by a second dose 24 hr later, prevented death of 60% of the mice. Pathologic symptoms of TAA intoxication (liver haemorrhage, elevation of amino acids in blood and tissues, diminution of liver spermidine and spermine concentrations, elevation of the activity of liver enzymes in the plasma) were significantly ameliorated by the treatment. The liver protective action of 5FMOrn is related to the elevation of ornithine concentration, as appears from the fact that other, less selective inactivators of ornithine aminotransferase, also produced some protection against acute intoxication with TAA, but not a structurally related compound with no effect on this enzyme.
Inhibition of Cumene Hydroperoxide‐Induced Lipid Peroxidation by a Novel Pyridoindole Antioxidant in Rat Liver Microsomes
Authors: Stefek Milan , Masarykova Maria , Benes Ludek
Published: March 2009

Abstract: The ability of stobadine, a novel pyridoindole antioxidant, to inhibit lipid peroxidation induced by cumene hydroperoxide was investigated in rat liver microsomes. In the micromolar range stobadine effectively inhibited lipid peroxidation as measured by the formation of thiobarbituric acid reactive products. The peroxidation‐related degradation of microsomal cytochrome P‐450 was prevented by stobadine in the same pattern. Another line of evidence in support of the antioxidant action of stobadine was given by its inhibition of cumene hydroperoxide‐induced oxygen consumption in microsomal incubations. Inhibition of lipid peroxidation was not a function of decreased bioactivation of cumene hydroperoxide, as stobadine did not affect the rate of cytochrome P‐450 dependent cleavage of cumene hydroperoxide. Neither had stobadine any effect on cytochrome P‐450 peroxidase function characterized by the rate of cumene hydroperox‐ide‐dependent oxidation of TMPD, and no direct spectral interaction with microsomal cytochrome P‐450 was observed in the micromolar region. We suggest that it is the ability of stobadine to scavenge alkoxyl and peroxyl radicals that is predominantly responsible for the observed antioxidant effect.
Pharmacokinetics in Rat of 3‐Chloro‐4‐(dichloromethyl)‐5‐hydroxy‐2(5H)‐furanone (MX), a Drinking Water Mutagen, after a Single Dose
Authors: Komulainen H. , Vaittinen S. ‐L. , Vartiainen T. , Lötjönen S. , Paronen P. , Tuomisto J.
Published: March 2009

Abstract: The pharmacokinetics of 3‐chloro‐4‐(dichloromethyl)‐5‐hydroxy‐2(5H)‐furanone (MX) was evaluated after a single oral or intravenous administration in the rats using 14C‐labelled compound. Twenty to 35% of the dose was absorbed into circulation from the gastrointestinal tract as assessed from the excretion in urine. The mean elimination half‐life of the radioactivity in blood (T1/2 k10) was 3.8 hr. Traces of radioactivity remained in the blood for several days. The tissues lining the gastrointestinal and urinary tract, kidneys, stomach, small intestines and urinary bladder contained the highest radioactivity. The activity declined slowest in the kidneys. Urine was the main excretion route. Seventy‐seven % of the total amount excreted appeared in urine in 12 hr and 90% in 24 hr. No radioactivity was exhaled in air suggesting that elimination through respiration did not occur. After an intravenous administration of 14C‐MX, the T1/2 k10, was much longer, 22.9 hr, and the total elimination half‐life (T1/2 β), 42.1 hr. The results indicate that MX is absorbed from the gastrointestinal tract to a considerable degree and it is excreted in urine very rapidly. A fraction of MX or its metabolites is retained in blood for a longer period of time. The pharmacokinetics of MX does not suggest extensive cumulation of MX in tissues after continuous exposure.