bluuebunny/crossref_metadata_2025 huggingface dataset:
Dose‐Effect Relationship of Disulfiram in Human Volunteers. II: A Study of the Relation between the Disulfiram‐Alcohol Reaction and Plasma Concentrations of Acetaldehyde, Diethyldithiocarbamic Acid Methyl Ester, and Erythrocyte Aldehyde Dehydrogenase Activity
Authors: Johansson Benny , Angelo Helle R. , Christensen Jens Knud , Møller Ib Walther , Rønsted Per
Published: March 2009

Abstract:The study was designed to elucidate the basic pharmacological and biochemical effects of the disulfiram dose (Antabus®) provoking disulfiram‐alcohol reaction (DAR) in 52 human volunteers after ethanol challenge. Disulfiram was given daily in increasing doses (1, 100, 200, and 300 mg) in successive 14 day periods, with ethanol challenge at the end of each period, until a DAR was achieved. Irrespective of dose (except the 1 mg dose), the DAR was always accompanied by almost complete inactivation (about 97%) of aldehyde dehydrogenase (ALDH) activity in erythrocytes, plasma concentrations of diethyldithiocarbamic acid methyl ester (Me‐DDC) in the range of 8‐472 nmol/l and accumulated plasma concentrations of acetaldehyde in the range of 7‐197 μmol/l. In four of the volunteers, the cardiovascular effects of the DAR were recorded as a decrease in diastolic blood pressure (14‐47 mmHg) and an increase in pulse rate (9‐40 beats/min.), accompanied by a two‐ to fourfold increase in the plasma concentrations of adrenaline and noradrenaline. The enzyme kinetics of ALDH in erythrocytes were regularly analysed in eight volunteers during DSF intake. In addition to the expected decrease in oxidizing capacity, the Kmvalues were also impaired, which suggests that the inhibitor is implicated in an active site directed reaction.
Mechanisms of Absorption of Inorganic Mercury from Rat Small Intestine. IV: Effect of Chelating Agents and Cysteine on Absorption of Mercuric Chloride in Situ and in Vitro
Authors: Endo Tetsuya , Nakaya Shozo , Kimura Ryohei
Published: March 2009

Abstract: The effects of chelating agents (citric acid, tartaric acid, penicillamine and ethylenediaminetetraacetic acid) and cysteine on the absorption of HgCl2 were investigated in rats. Perfusion of the small intestine showed that the chelating agents and cysteine decreased the absorption of HgCl2 depending on their stability of constants with Hg2+, under the predominant conditions of water absorption and secretion. The difference in absorption of HgCl2 between both conditions was inversely correlated with their logarithmic stability constant values. These agents decreased the transport of HgCl2 through the everted intestinal wall and the uptake of HgCl2 by the intestinal brush border membrane in a similar manner. From these results, it is suggested that the chelating agents and cysteine decrease the absorption of HgCl2 through the pores of the brush border membrane due to the solvent drag effect.
Inhibitory Effect of Aclarubicin on Endothelium‐Dependent Relaxation of Rat Aorta
Authors: Wakabayashi Ichiro , Sakamoto Kunihiro , Hatake Katsuhiko
Published: March 2009

Abstract: The effects of aclarubicin on endothelium‐dependent and ‐independent vasorelaxations were investigated in aortic strips from rats. Aclarubicin (5.9‐23.6 μM) inhibited endothelium‐dependent relaxation and the increment of the cyclic GMP level in aortic strips in response to acetylcholine but not the endothelium‐independent relaxation and the increase of cyclic GMP level in response to sodium nitroprusside. Aclarubicin also inhibited endothelium‐dependent relaxations in response to ATP and calcium ionophore A23187. These results suggest that aclarubicin can inhibit endothelium‐dependent relaxation by acting somewhere distal to receptor stimulation in vascular endothelial cells.
Pharmacokinetic Aspects of Inorganic Nitrate Ingestion in Man
Authors: Cortas Najwa K. , Wakid Nabil W.
Published: March 2009

Abstract: Inorganic nitrate and nitrite concentrations were monitored simultaneously in the plasma, erythrocytes, saliva and urine of five subjects following an oral dose of NaNO3 (470 μmol per kg body weight). There was an average 25‐fold increase in plasma nitrate only 10 min. after ingestion. Its concentration rose to a peak level of 1.83 mM in 40 min., a value 49 times the preload level. Erythrocyte nitrate followed a similar pattern, but remained at about two thirds of the plasma values. Salivary nitrate showed a positive correlation with plasma nitrate and averaged 9 times the plasma level during 3 hr following ingestion. This is evidence of a concentration‐dependent active secretion by the salivary glands. The mean nitrate clearance was 25.8±2.85 (S.E.M.) ml/min. corrected for a body area of 1.73 m2 (n = 17). The urinary nitrate/creatinine ratio increased 25 to 70 times after loading. These results indicate a predominantly tubular excretion of nitrate. Nitrite was not detectable in any of the body fluids studied except saliva, where it appeared to increase at the expense of nitrate.
Glucuronidation of 7‐Hydroxy‐4‐methylcoumarin by Microsomes from Normal and Diseased Human Livers
Authors: Irshaid Yacoub , Gharaybeh Kamal
Published: March 2009

Abstract:Glucuronidation of 7‐hydroxy‐4‐methylcoumarin (7‐H‐4‐MC) by microsomal UDP‐glucuronosyltransferases from 12 human liver biopsy samples was studied. Glucuronidation rates were highest for livers with mild cholestasis while those for livers with mild fatty changes were similar to normal livers. The lowest rates were exhibited by livers showing primary or metastatic carcinoma on histological examination. Thus, glucuronidation of not only bile acids but also of other substrates such as 7‐H‐4‐MC may be elevated in cholestasis. These results are also consistent with other studies stating that glucuronidation might be spared in certain mild hepatic diseases.
Effects of Enoxacin and its Combination with 4‐Biphenylacetate, an Active Metabolite of Fenbufen, on Population Spikes in Rat Hippocampal Slices
Authors: Ito Tsugutaka , Miura Yoshiki , Kadokawa Toshiaki , Hori Seiji , Shimada Jingoro , Miyahara Tadashi
Published: March 2009

Abstract: The effects of enoxacin, a new quinolone antibacterial agent, and its combination with 4‐biphenylacetate (BPA), an active metabolite of the non‐steroidal antiinflammatory agent fenbufen, were examined on population spikes induced by electrical stimulation of the stratum radiatum in the CA1 pyramidal cell layer in rat hippocampal slices. Enoxacin (10−4 M) and bicuculline (lo−6 M) increased the amplitude of the population spikes and anew elicited the second spikes (latency: 10 msec.), while BPA (10−5 M) decreased the amplitude of the population spikes. However, the combination of enoxacin (10−6, 10−5 M) with BPA (10−5 M) elicited the second spikes or epileptiform bursts with an increase of the population spike amplitude. The dose‐response relationships showed that the effect of enoxacin was 100 times potentiated in the presence of BPA (10−5 M). The second spikes induced by enoxacin (10−4 M) were suppressed by muscimol (10−6 M) and baclofen (10−6 M), but not by clorazepate (5 × 10−5 M) and pentobarbital (5 × 10−5 M). The second spikes induced by bicuculline (10−6 M) were suppressed by these four drugs. The second spikes by the combination of enoxacin (10−6 M) with BPA (10−5 M) were suppressed by muscimol (5 × 10−6 M), but not by clorazepate (5 × 10−5 M). These results suggest that the combination of enoxacin with BPA exerts a drug interaction to elicit the second spikes or epileptiform bursts with its mode of action different from that of bicuculline.
Different Effects of Paraquat on Microsomal Lipid Peroxidation in Mouse Brain, Lung and Liver
Authors: Hara Shuichi , Endo Takahiko , Kuriiwa Fumi , Kano Sadao
Published: March 2009

Abstract:Paraquat stimulates NADPH‐Fe2+‐dependent microsomal lipid peroxidation in mouse brain and strongly inhibits it in the liver. In lung microsomes, the lipid peroxidation was stimulated by paraquat at 10−4M, but not at higher doses. An antioxidant action of paraquat seemed to account, at least in part, for the lack of stimulation in lung microsomes, but it was inappropriate to explain the result in hepatic microsomes. There was no apparent correlation between the effects of paraquat on the lipid peroxidation and on the activity of NADPH‐cytochrome P‐450 reductase, the enzyme which initiates redox cycling of paraquat, resulting in generation of active oxygen species. In fact, the effect of paraquat on the lipid peroxidation was independent of paraquat radical production, an intermediate in the cycle. However, the inhibitory potency of N‐ethylmaleimide on NADPH‐cytochrome P‐450 reductase activity paralleled that on the lipid peroxidation stimulated by paraquat in brain and lung. These findings indicate that the effect of paraquat on microsomal lipid peroxidation differs among the organs and that other factors, besides NADPH‐cytochrome P‐450 reductase, might be involved in the stimulation of lipid peroxidation by paraquat.
Chronic Lead Poisoning Treated with Dimercaptosuccinic Acid
Authors: Grandjean Philippe , Jacobsen Ib Abildgaard , Jørgensen Poul Jørgen
Published: March 2009

Abstract:A 54‐year‐old male with chronic lead poisoning was treated with 2,3‐dimercaptosuccinic acid (DMSA). A daily dosage of 30 mg/kg body weight for three days and 20 mg/kg for four days resulted in a decrease of the blood‐lead concentration (B‐Pb) from 3.7 to 0.7 μmol/l; the total amount of lead excreted in the urine during the first seven 24 hr periods was 75 μmol. After the treatment, B‐Pb slowly increased to 3.3 μmol/l. A second treatment was then initiated and resulted in similar changes in B‐Pb. However, during the third treatment, the patient developed a mucocutaneous vesicular flare; the eruptions faded after cessation of the chelation therapy, but could be provoked by DMSA doses of 10 mg/kg and above. Despite the small number of treatment courses, the patient showed obvious mental improvement and reported less headache and improved memory. Thus, DMSA is an efficient chelator that results in a rapid, though temporary decrease in B‐Pb. Although oral treatment with this chelator may be supervised from the out‐patient clinic, careful monitoring for potential side effects is recommended.
Effects of Clodronate and Pamidronate on Splenic and Hepatic Phagocytic Cells of Mice
Authors: Mönkkönen Jukka , van Rooijen Nico , Ylitalo Pauli
Published: March 2009

Abstract:Bisphosphonates inhibit the activity of osteoclasts and conceivably also macrophage activity. Administered in hypoosmotic solution, clodronate (dichloromethylene bisphosphonate) forms complexes with the iron of haemolysed erythrocytes and subsequently accumulates in splenic and hepatic macrophages. Pamidronate (3‐amino‐1‐hydroxypropylidene bisphosphonate) also accumulates in the spleen and liver of mice and rats even when injected in isoosmotic solution. In the present study, the effects in mice of uncomplexed clodronate, clodronate‐iron complex, clodronate‐liposomes, and pamidronate on splenic and hepatic macrophagesin vivowere studied by an enzyme‐histochemical method. Intracellular free clodronate released in the cells after phagocytosis of clodronate‐liposomes virtually eliminated all macrophages from spleen, and also Kuppfer cells from liver. Clodronate given in hypoosmotic vehicle had no effect on these cells, although it was taken up by them. Clodronate in isoosmotic vehicle, considered as uncomplexed clodronate, neither accumulates in nor affects the macrophages. Pamidronate, however, decreased the number of the cells also after isoosmotic injection. Thus, the capability of bisphosphonates to sequestrate intracellular calcium may explain their effects on macrophages.
Behavioural and Biochemical Effects of Subchronic Treatment with Raclopride in the Rat: Tolerance and Brain Monoamine Receptor Sensitivity
Authors: Ahlenius Sven , Ericson EvaLena , Högberg Kerstin , Wijkström Agneta
Published: March 2009

Abstract:Male Sprague‐Dawley rats were treated with the dopamine (DA) D2receptor blocking agent raclopride 0.5 or 8.0 mg kg−1subcutaneously (1.0 and 16.0 μmol kg−1, respectively), twice daily for 21 days. The animals treated with raclopride gained weight at the same rate as saline controls, and gross observation did not indicate any behavioural abnormalities due to the subchronic raclopride treatment. Possible changes in brain DA receptor sensitivity due to prolonged blockade of DA receptors were evaluated in behavioural and biochemical models. There were no effects on locomotor activity, as observed by means of photobeam‐equipped activity cages, 24 hr or 72 hr after withdrawal of 0.5 or 8.0 mg kg−1subchronic raclopride treatment. Twenty‐four hr after withdrawal of the raclopride treatment there was an increased post‐synaptic DA receptor sensitivity as evidenced by increased behavioural and biochemical responses to apomorphine, and by an attenuated response to acute raclopride treatment, 0.1 mg kg−1. Thus, there was an increase in locomotor activity by the apomorphine treatment in animals pretreated with the 8 mg kg−1dose, as compared to the response obtained in saline controls. Furthermore, the suppression of locomotor activity in saline controls produced by acute raclopride treatment was dose‐dependently antagonized by the raclopride pretreatment and this also applied to the increase in striatal DOPAC levels produced by acute raclopride treatment. Finally, there was an increased DA receptor sensitivity presynaptically as evidenced by an enhanced effect on striatal DOPA levels by apomorphine in rats treated with NSD 1015 and reserpine. Thus, the increase in DOPA accumulation induced by reserpine was partially antagonized by treatment with apomorphine, 0.05 mg kg−1, and this effect was enhanced in animals pretreated with the highest dose of raclopride (8 mg kg−1). This effect persisted for at least 72 hr following withdrawal of raclopride treatment. Taken together, the present results shows that withdrawal of subchronic raclopride treatment with 8.0, but not 0.5, mg kg−1produces an increased response to apomorphine challenge pre‐ and postsynaptically, and this effect was observed for up to 72 hr after withdrawal of raclopride treatment. Both pretreatment doses of raclopride (0.5 and 8.0 mg−1) produce behavioural and biochemical signs of tolerance to the treatment.
Renal Handling and Effects of Salicylic Acid in the Isolated Perfused Rat Kidney
Authors: Cox P. G. F. , Moons W. M. , Russel F. G. M. , van Ginneken C. A. M.
Published: March 2009

Abstract:The renal handling of salicylic acid (SA) and its effects on renal function were studied in the isolated perfused rat kidney (IPK). The renal handling of SA is dominated by reabsorption and only a small fraction of the filtered SA is excreted into the urine. Reabsorption is a passive process and is dependent on urinary pH. Because of the extensive reabsorption, no decrease in perfusate concentration can be observed in the course of the IPK experiment. SA accumulated slightly in the IPK and this accumulation is concentration dependent. Small amounts of SA were converted to salicyluric acid (SU), the glycine conjugate of SA. SA concentrations higher than 100 μg/ml caused an immediate increase in urinary flow and in fractional excretion of sodium, potassium, chloride and calcium. Fractional excretion of glucose increased gradually. Glomerular filtration rate, renal perfusion flow, renal pressure and fractional excretion of magnesium were not affected by SA. The effects were dependent on the SA concentration. Although SA is a classical non‐steroidal antiinflammatory drug (NSAID), its influence on renal function appears to be different from other NSAIDs which are usually associated with a reduction in urinary flow and salt excretion.
Ligand Structural Specificity of GABAAReceptors in Guinea Pig Ileum
Authors: Kristiansen Uffe , Fjalland Bjarne
Published: March 2009

Abstract:The ligand structural specificity of ileal GABAAreceptors was examined using the strength and half‐life of contractions in guinea‐pig myenteric plexus‐longitudinal muscle preparations. The agonists used differ by more than a factor of 1000 in affinity to central GABAAreceptors and include both conformationally flexible and restricted molecules as well as pairs of enantiomers. The overall correlation between ileal contractile activity and rat brain receptor affinity was poor (r = 0.75), but within groups of conformationally flexible or conformationally restricted molecules a high correlation was found (r>0.9999). When comparing data for ileal contractile activity with available data for agonist activity in the CNS no difference between ligand specificity of ileal and central GABAAreceptors was apparent with the present range of ligands. The half‐lives of ileal contractile responses were found to decrease with increasing GABABagonist activity
Effects of 3,3′,4,4′‐Tetrachlorobiphenyl (TCB) on Ovaries of Foetal Mice
Authors: Rönnbäck Curt
Published: March 2009

Abstract:Female C57/B1 mice were administered 3,3′,4,4′‐tetrachlorobiphenyl (TCB) on the 13th day of pregnancy. The TCB‐amounts ranged between 1.5‐15 mg/kg b. wt. and were given intraperitoneally. Ovaries ofin uterotreated females aged 28 days were prepared and microscopically analysed for the number of oocytes and follicles. No effect of TCB was observed until the dose of 15 mg giving a reduction of the germ cell number of the order of 40‐50 per cent of the control figures. It was noticed that this decrease appeared in all stages of oocytes and follicles contrary to the situation after an exposure for ionizing irradiation. No significant change in the reproductive capacity was observed during a five months test period.
Lithium Modifies Convulsions and Brain Phosphoinositide Turnover Induced by Organophosphates
Authors: Savolainen Kai M. , Muona Outi , Nelson Stanley R. , Samson Fred E. , Pazdernik Thomas L.
Published: March 2009

Abstract:Inositol‐1‐phosphate (InslP), an index of phosphoinositide (PI) turnover, was measured in frontal and piriform cortices, caudate, thalamus, hippocampus and cerebellum in saline or LiCl (5 m Eq./kg) pretreated rats 60 min. after graded doses of DFP, paraoxon, or soman. DFP only produced bursts of convulsive activity whereas both paraoxon and soman produced prolonged tonic‐clonic convulsions. All three organophosphates (OP) produced convulsions at a lower dose in LiCl than in saline pretreated rats. Regional InslP correlated better with the presence or absence of convulsions than with the dose of paraoxon or soman. This was true both in saline and LiCl pretreated rats. In saline pretreated non‐convulsing rats, there was a cholinergic increase (1.5‐2.0 X) in InslP in all brain regions except cerebellum after OP injection. In saline pretreated convulsing rats, there was a marked seizurogenic further increase in InslP; highest in caudate (8 X) and cortex (6 X). In LiCl pretreated nonconvulsing rats, the OP‐induced cholinergic increase in InslP was significant only in caudate, thalamus and hippocampus. In LiCl pretreated convulsing rats, the further seizurogenic increase in InslP was less than in saline pretreated rats except in thalamus and hippocampus. Thus, OP produce both a cholinergic and a seizurogenic increase in PI turnover. These data suggest that increased PI turnover in the hippocampus may indicate a lithium‐induced lowering of the seizure threshold for OP in limbic regions.
Influence of Concentration and Injection Volume on the Bioavailability of Subcutaneous Growth Hormone: Comparison of Administration by Ordinary Syringe and by Injection Pen
Authors: Blok G. J. , van der Veen E. A. , Susgaard S. , Larsen F.
Published: March 2009

Abstract:In order to study whether the bioavailability of subcutaneously injected growth hormone (GH) is dependent on the concentration/volume injected, the relative GH bioavailability was evaluated in 14 GH‐deficient patients. In a cross‐over study the patients received, in random order two separate subcutaneous GH injections (Norditropin®) 4 IU administered by means of an ordinary syringe (4 IU/ml) and an injection pen with cartridge (Nordiject 24®) (12 IU/ml). Blood samples were drawn over a 14 hr period and assayed for serum concentrations of GH and IGF‐I. The mean value (±S.D.) of the relative absorption fraction (Fpen/sy) was 1.09±0.39. Mean values of Cmaxwere 8.6 ng/ml±4.8 and 8.3 ng/ ml±7.5 for syringe and pen respectively. Corresponding values for Tmaxwere 311 min.±131 for syringe and 309 min.±104 for pen. Although a considerable interindividual variation was seen, the relative absorption fraction did not differ significantly from 1 (2 P=0.78). Further there was no significant difference in neither Cmax(2 P=0.39) nor Tmax(2 P = 0.55). IGF‐I serum profiles tended to be higher following syringe compared to pen injection (2 P = 0.054). On the basis of this study we conclude that in this dosage regimen, GH bioavailability following pen injection equals that of injection by syringe (i.e. no effect of a three fold increase/decrease in GH concentration/volume respectively).
Atipamezole, Benzodiazepines, Bicucullin and Tifluadom Antagonize the Effect of TRH on Rat Duodenum and Displace it from Brain and Anterior Pituitary Receptors
Authors: Järvinen Asko
Published: March 2009

Abstract: The mechanism of action of the TRH induced inhibition of contractions of the transmurally stimulated rat duodenum has been studied. The effect of TRH was not antagonized by atropine, pentolinium, phenoxybenzamine, sotalol, methysergide, domperidone, diphenhydramine, cimetidine, aminophylline, antazolin, indomethacin, morphine, naloxone or tetrodotoxin. In contrast, the adrenergic α2‐antagonist atipamezole, the benzodiazepines chlordiaxepoxide and midazolam or GABA‐A‐antagonist bicucullin but not picrotoxin or SR‐95531 attenuated the response to TRH. An opioid‐kappa‐receptor agonist having benzodiazepine structure, tifluadom, but not MR 2034 also diminished the response to TRH. However, these actions were not modified by the α2‐agonist medetomidine, benzodiazepine antagonist flumazenil, GABA‐agonists muscimol or baclofen or naloxone, respectively. While the binding of [3H][3‐Me‐His2]TRH to the rat anterior pituitary, hypothalamus, cortex and brainstem homogenates was saturable and of high affinity, no saturable binding was observed in the duodenal smooth muscle. Agents that were effective in the duodenal preparation displaced [3H][3‐Me‐His2]TRH from its binding sites in brain homogenates and the inhibitory constants (Ki) were (in μM): 0.038‐0.107 (TRH), 0.19‐5.8 (chlordiazepoxide), 0.021‐8.9 (midazolam), 1.5‐17 (tifluadom), 60‐210 (bicucullin) and 150‐530 (atipamezole). Atipamezole, bicucullin and chlordiazepoxide caused competitive displacement indicated by the increased KD of the labelled ligand but no change in the Bmax while tifluadom increased KD and decreased Bmax. It is concluded that the inhibitory effect of TRH on the contractions of the duodenal smooth muscle is mediated directly by the smooth muscle and it is apparently specific for TRH. The competitive displacement of [3H][3‐Me‐His2]TRH binding in brain homogenates by benzodiazepines, bicucullin and atipamezole suggest a similar mechanism for their antagonistic effect of the TRH‐induced inhibition of duodenal contractions.
Studies on Active Transport of (E)‐10‐Hydroxynortriptyline in the Kidney and Brain of Rats: Effects of Propranolol and Quinidine
Authors: Otani Koichi , Kaneko Sunao , Bertilsson Leif
Published: March 2009

Abstract:Studies in humans have given strong support of an active transport of (E)‐10‐hydroxynortriptyline ((E)‐10‐OH‐NT) in the kidney and from the cerebrospinal fluid. After 3 days of intraperitoneal injections of (E)‐10‐OH‐NT (10 mg/kg t.i.d.) in a rat model, we investigated the effect of propranolol and quinidine (25 and 2.5 mg/kg injected 6 times during day 3) on the concentrations of (E)‐10‐OH‐NT in urine, plasma (total and unbound) and brain. In a group of control rats the renal clearance of (E)‐10‐OH‐NT varied 10‐fold between rats, but was reproducible from Day 2 to Day 3 (r=0.83; n=8; p<0.05). Quinidine markedly decreased the renal clearance of both total and unbound (E)‐10‐OH‐NT from plasma, while the effect of propranolol was less pronounced. There was no difference in the ratio of (E)‐10‐OH‐NT concentrations in brain and plasma (unbound) between treated and control rats. We conclude that (E)‐10‐OH‐NT is actively secreted in the rat proximal tubule and that the activity of this system varies between rats, but is constant in the individual rat. Quinidine, and to a less extent propranolol, inhibits this renal secretion. By the present methodology we could not demonstrate an active transport of (E)‐10‐OH‐NT from brain to blood in the rat. Studies using other methods are needed to further elucidate this.
Irreversible Effects in Rats of Toluene (Inhalation) Exposure for Six Months
Authors: Ladefoged Ole , Strange Poul , Møller Arne , Lam Henrik R. , Østergaard Grete , Larsen Jens‐Jørgen , Arlien‐Søborg Peter
Published: March 2009

Abstract: The irreversible CNS effects of six months' exposure to toluene (0, 500, and 1500 p.p.m.) in rats was studied applying a multi‐disciplinary approach. After an exposure‐free period, neurobehavioural, morphometric, pathological, and biochemical examinations were performed. No neurobehavioural or gross pathological changes were found. Morphometric measurements did not show loss of neurones. At 500 p.p.m. the mean nuclear volume and mean perikaryonal volume and the variation of the values of these parameters was increased in the exposed groups compared to the controls. Noradrenaline (NA), dopamine (DA), and 5‐hydroxytryptamine (5‐HT) levels were significantly changed in various brain regions. It is concluded that this investigation failed to reveal overt toluene‐induced CNS‐neurotoxicity, however, certain irreversible effects were found which further add to the accumulating evidence of the chronic CNS‐neurotoxicity of toluene.
Effect of Selected Neuroleptic Agents and Stereo‐Isomeric Analogues on Virus and Eukaryotic Cells
Authors: Kristiansen Jette E. , Andersen Leif P. , Vestergaard Bent Faber , Hvidberg Eigill F.
Published: March 2009

Abstract:Chlorpromazine, cis(Z)‐chlorprothixene (Truxal®), and the non‐neuroleptic trans(E)‐chlorprothixene and trans(‐E)‐flupenthixol were studiedin vitrofor possible antiviral effect on Herpes simplex virus 2 and for toxic effect on human diploid fibroblasts. Based on an enzyme‐linked immunosorbent assay (ELISA) antiviral activity was demonstrated for all the compounds in the concentration range 0.39 μg/ml‐25 μg/ml. A cell‐toxic effect was shown in the higher concentration range for all the compounds except cis(Z)‐chlorprothixene. A cell‐stimulatory effect was also detected at the lower concentration range (about 3.13 μg/ml) for all compounds. Thus both cell stimulation and antiviral effect can be found for the same agent within the same concentration range. The results point to the possibility of creating different antiviral drugs ‐ which would also include a cell‐stimulatory activity ‐ among psychopharmacological drugs and their stereo‐isomeric analogues.
Effects of Lipophilic Complex Formation on the Uptake and Distribution of Some Metals in Fish
Authors: Tjälve Hans , Gottofrey James
Published: March 2009

Abstract:Dithiocarbamates, xanthates, dialkyldithiophosphates and pyridinethiones are groups of compounds which can form lipophilic complexes with heavy metals. These compounds are widely used in industry and in agriculture and forestry and may pollute the aquatic environment. We have exposed fish (brown trouts) to substances belonging to these groups of compounds together with heavy metals (Cd2+, Ni2+, Hg2+, CH3‐Hg+or Pb2+) and then examined the uptake of the metals in the tissues of the fishes. Some of the examined complexing substances were found to cause highly increased tissue levels of the metals in the trouts. However, the enhancing effects varied for different complexing substances and for different metals. A facilitated penetration of the lipophilic complexes over the gill membranes and cellular membranes in other tissues may underlie the increments in the tissue levels of the metals. The lipophilicity and the stability of the complexes may be of importance for the effects of the substances on the disposition of the metals. Studies by other authors, in fishes as well as in other aquatic organisms, have also shown enhanced metal accumulation by compounds forming lipophilic complexes. It is considered that this type of interaction may have important implications for the behaviour of metals in aquatic ecosystems.
Effect ofin VivoChromate, Acetone and Combined Treatment on Rat Liverin VitroMicrosomal Chromium(VI) Reductive Activity and on Cytochrome P450 Expression
Authors: Mikalsen Arne , Alexander Jan , Andersen Rolf A. , Ingelman‐Sundberg Magnus
Published: March 2009

Abstract:Cytochrome P450 (P450IIE1) in rat has previously been shown to exhibit high chromate [Cr(VI)] reductase activity (Mikalsenet al.1991). The present study reports on the effect of chromate treatmentin vivoin rats and on the modulating effect of acetone+fasting on chromium(VI) toxicity. No effect of intraperitoneal injection with 5 mg chromate/kg was observed, whereas 15 mg chromate/kg decreased the liver microsomal Cr(VI) reductase activity by about 30% inin vitromicrosomal incubations. In addition, the P450 and cytochrome b5contents were decreased by about 30% and 25% respectively. Acetone+fasting caused increases of total microsomal P450 and cytochrome b5contents, associated with similar increases in apoproteins P450IIE1 and P450IIB1+2, and their corresponding mRNA, and apoprotein NADPH‐P450 reductase, as well as NADPH‐P450 reductase and microsomal Cr(VI) reductive activities. Related to acetone+fasting alone, when given in combination with chromate (15 mg/kg) the Cr(VI) reductive activity was decreased by about 30%, associated with decreases in the P450 and cytochrome b5contents, 65% and 35% respectively. This further reduced the apoprotein levels of P450IIB1+2, P450IIE1, and NADPH‐P450 reductase to 90%, 60%, and 40%, respectively, and the mRNA levels of P450IIB2 and P450IIE1. No effect was observed on NADPH‐P450 reductase activity. This dose also caused some macroscopic alterations in the liver. In contrast, the P450IIE1 apoprotein level in the lung was apparently stabilized or even increased by chromate in rats treated with acetone+fasting. The results show that acetone+fasting causes induction of microsomal Cr(V) metabolism and increases chromium toxicity. Chromate does not induce its own metabolism in liver and interferes, probably in a complex way, with P450 enzymes and their gene expression, especially when induced.
Distribution of Mercury in Rabbits Subchronically Exposed to Low Levels of Radiolabeled Methyl Mercury
Authors: Petersson Kierstin , Dock Lennart , Söderling Karin , Vahter Marie
Published: March 2009

Abstract: The metabolism of methyl mercury (MeHg) has been studied in rabbits administered 203Hg‐labeled methyl mercuric chloride, 0.125 μmol/kg body weight, twice a week for 9 weeks, by intravenous injection. Twelve weeks after cessation of treatment, about 54% of the administered dose had been excreted in faeces and 5% in urine. After one week, the highest concentration of 203Hg was found in fur (8.6 nmol Hg/g). Substantially lower concentrations were found in kidney (2.5 nmol/g), liver (0.9 nmol/g), brain (0.4 nmol/g), muscle (0.3 nmol/g) and blood (0.1 nmol/g). The rate of elimination of 203Hg from brain, muscle and blood was faster (t1/2 about 12 days) than that from kidney and liver (t1/2 about 28 days). The relative amount of inorganic Hg in kidney and liver increased with time after cessation of treatment. The highest fractions were 85 and 70%, respectively. In brain, no significant demethylation of MeHg could be detected.
Effects of Simultaneous Ethanol and Toluene Exposure on Nerve Cells Measured by Changes in Synaptosomal Calcium Uptake and (Ca2+/Mg2+)‐ATPase Activity
Authors: Edelfors Sven , Ravn‐Jonsen Andree
Published: March 2009

Abstract: The effect of simultaneous exposure of rats to toluene and ethanol on synaptosomal calcium uptake and (Ca2+/ Mg2+)‐ATPase activity was studied. Rats were exposed to 500 p.p.m. toluene by inhalation for 12 hr a day during four weeks. During the exposure period, the rats had access to 5% sucrose solution containing 20% ethanol or to 5% sucrose solution alone. Rats drinking ethanol exhibited a smaller weight gain than rats drinking water alone. Furthermore, rats exposed simultaneously to toluene and ethanol had a higher ethanol intake than unexposed rats. The toluene exposure caused a higher synaptosomal calcium uptake in vitro. Ethanol intake did not change the synaptosomal calcium uptake in vitro. The synaptosomal calcium uptake in rats exposed to toluene and ethanol was nearly identical to that measured in control rats. In vivo exposure to toluene, or ethanol, or toluene/ethanol simultaneously did not affect the (Ca2+/ Mg2+)‐ATPase activity in vitro. Incubation with toluene in vitro decreased the (Ca2+/Mg2+)‐ATPase activity in a concentration dependent manner. Ethanol had only a slight effect on the enzyme. Simultaneous incubation with toluene and ethanol showed an antagonistic effect of ethanol on the toluene inhibition of the ATPase activity.
Dithranol (Anthralin)‐induced Skin Irritation in C57BL/6, NMRI and SENCAR Mice
Authors: Viluksela Matti , Kosma Veli‐Matti
Published: March 2009

Abstract:Dithranol‐induced skin irritation was compared in C57BL/6, NMRI and SENCAR mice, the strains representing different sensitivity to tumour promotion. Skin irritation was assessed using ear thickness and skin weight measurements, visual estimation of back skin irritation and histopathology. Both single and repeated applications of dithranol caused a delayed skin irritation resulting in the maximal response between 7‐11 days after the beginning of the treatment. Contrary to the findings with 12‐O‐tetradecanoyl‐phorbol‐13‐acetate (TPA), C57BL/6 mice were the most sensitive and SENCAR mice the most resistant to the dithranol‐induced skin irritation up to 30 days from the beginning of the treatment. NMRI mice were intermediate. Differences were found in the ear swelling, epidermal hyperplasia, amount of inflammatory cell infiltrate and skin ulceration. During repeated treatment of about 40 days, however, the responsiveness of SENCAR mice increased over that of C57BL/6 and NMRI mice. SENCAR mice had also more epidermal hyperplasia than the other strains at the end of the 74 day period of 3 times weekly applications. The magnitude of epidermal hyperplasia after long term treatment seems to correlate with the sensitivity to tumor promotion in the different mouse strains.
The Uptake of Bupivacaine in anin situIsolated Perfused Rabbit Lung Preparation
Authors: Palazzo M. G. A. , Kalso E. , Argiras E. , Madgwick R. , Sear J.
Published: March 2009

Abstract:A double indicator technique has been used in anin situisolated perfused rabbit lung model to examine the first pass effect of the lung on systemic bupivacaine concentrations. Bupivacaine (0.5 mg/kg) was given in two consecutive boluses to sixin situisolated perfused New Zealand White rabbit lung preparations. The mean recovery (first bolus) of bupivacaine was 62.6% ± 6.3 (S.E.M.), and 63.7% ± 10.2 (second bolus), suggesting bupivacaine accumulation in the lung. The average mean transit time for bupivacaine was 280.5% ± 24.1 and 264.8% ± 36.7 longer than ICG (Indocyanine Green) following the first and second boluses respectively (P < 0.01). There were no differences in the first pass effect of the lung between the first and second boluses of bupivacaine. The profiles of the bupivacaine concentrations suggest that uptake is followed by accumulation and later back diffusion. This has implications for conditions that decrease the uptake and therefore increase the risk of systemic toxicity.
Antiangiogenic Effect of Heparin and Other Sulphated Glycosaminoglyycans in the Chick Embryo Chorioallantoic Membrane
Authors: Jakobson Åke M. , Hahnenberger Rudolph
Published: March 2009

Abstract:The effect of heparin and other sulphated glycosaminoglycans on normal capillary growth was studied in the chick embryo chorioallantoic membrane, with or without hydrocortisone. Contrary to previous reports, heparin was shown to have an antiangiogenic effect in itself, and an additive effect was obtained when it was combined with hydrocortisone. Heparan sulphate also had an antiangiogenic effect in the chorioallantoic membrane, while keratan sulphate, dermatan sulphate or chondroitin sulphate had no such effect. Copper ions, added in small amounts, did not influence the antiangiogenic effect of heparin, and nor did iron, zinc and magnesium ions, and EDTA.
Acute Hepatotoxicity after High‐Dose Methotrexate Administration to Rats
Authors: Bremnes R. M. , Smeland E. , Huseby N.‐E. , Eide T. J. , Aarbakke J.
Published: March 2009

Abstract:Acute hepatotoxicity after administration of 10‐1000 mg/kg methotrexate (MTX) to rats was studied by monitoring serum transaminases, liver morphology, and disposition kinetics of MTX and 7‐hydroxy‐methotrexate (7‐OH‐MTX). Half the control rats and rats administered 1000 mg/kg MTX, had their bile duct cannulated. One to 2 hr after administration of 1000 mg/kg MTX, 50% of MTX treated bile‐drained rats (Ebc) developed cholestasis despite similar or larger initial bile flow rates than those which did not develop cholestasis (Ebn, controls). In Ebcanimals, peak serum ASAT and ALAT levels were 6‐ and 4‐fold higher than that of the control rats, and morphologically, prominent hepatocytic changes and grossly dilated bile canaliculi were found. Immediately prior to cholestasis, the Ebcanimals reached biliary 7‐OH‐MTX levels (8.3 ± 1.3 raM, mean ± S.E.M.) which were equivalent to the threshold level for precipitation of 7‐OH‐MTX in rat bilein vitro, and 3‐fold higher than the corresponding levels of 7‐OH‐MTX in the bile of Ebnrats. Ninety‐five % of the drug in the precipitated material was 7‐OH‐MTX. Hence, 7‐OH‐MTX may play a role in acute MTX hepatotoxicity, a dose‐limiting toxicity that may not be counteracted by leukovorin rescue.
The Influence of Potassium Concentration on the Inhibitory Effect of Amiodarone on Guinea‐Pig Microsomal Na+‐K+‐ATPase Activity
Authors: Almotrefi Abdulrahman A. , Dzimiri Nduna
Published: March 2009

Abstract: The effects of varying incubation K+ concentration on the inhibitory action of amiodarone on the Mg2+‐dependent ATP hydrolysis by myocardial Na+‐K+‐ATPase (EC 3.6.1.3) were studied in guinea pig heart preparations. In the first part of the study, it was established that the activity of the enzyme increased with growing concentrations up to approximately 20 mM K+. The concentration‐response relationships for amiodarone were investigated in incubation media containing 2.5, 5.0 and 10 mM K+ respectively. Amiodarone exhibited similar concentration‐dependent inhibitory effects in the range of 0.01 nM −80 μM at 2.5 mM, 0.13–150 μM at 5.0 mM and 0.3–700 μM at 10.0 mM K+. The corresponding IC50 values were 10.4 ± 3.2 μM at 2.5 mM, 28.3 ± 7.6 μM at 5.0 mM and 33.3 ± 9.2 μM at 10.0 mM K+, respectively. Thus, reduction in the K+ concentration from the “standard” 5.0 to 2.5 mM was accompanied by a significant right‐to‐left shift in the inhibitory potency of amiodarone, the effective concentrations being shifted from uM into nM ranges. Increasing K+ concentration to 10 mM on the other hand attained opposite but less remarkable effects. The results show that the in vitro inhibition of myocardial Na+‐K+‐ATPase activity by amiodarone is related to the K+ concentration of the incubation medium. These effects may be pertinent to the mechanism by which this drug interferes with the electrogenic Na+/K+ pump activity of the enzyme, thereby probably contributing to the mechanism(s) responsible for some of its cardiac actions.
Effect of Furosemide, Hydrochlorothiazide and Sodium Restriction on Rat Adrenoceptors
Authors: Brørs Odd
Published: March 2009

Abstract:The interaction of thiazide diuretics and furosemide with adrenoceptors was investigated in normal ratin vivoby determining the effect of sodium‐deficient diet alone or combined with hydrochlorothiazide or furosemide on adrenoceptors in heart, kidney and skeletal muscle. In addition, interaction of diuretics with renal adrenoceptorsin vitrowas investigated. Sodium‐deficient diet alone retarded growth significantly, and this effect was increased by simultaneous treatment with furosemide 10–4. mg/kg body weight and day subcutaneously. No consistent alteration was demonstrated in density or affinity of α1‐, α2‐ and β‐adrenoceptors due to thein vivotreatment.In vitro, furosemide inhibited the equilibrium specific binding of radioligands to α1‐,α2‐ and β‐adrenoceptors to rat kidney paniculate fraction concentration‐dependently. Furosemide increased Kd(equilibrium dissociation constant) and reduced Bmax(number of specific binding sites) of the radioligands as determined by Scatchard analysis of binding saturation data. The Pseudo‐Hill coefficient of the inhibition by furosemide of125I‐iodocyanopindolol binding was 1.47, indicating a complex interaction consistent with a non‐competitive inhibition. In conclusion, the results do not support the hypothesis that sodium deficiency alone or with diuretic treatment for one week alters tissue adrenoceptors in the normal rat. The pattern of inhibition by furosemide of ligand binding to adrenoceptors suggests that furosemide binds to an allosteric site on the receptors or to an adjacent macromolecule.
Calcium Antagonistic Properties of the Sesquiterpene T‐Cadinol: A Comparison with Nimodipine in the Isolated Rat Aorta
Authors: Claeson Per , Zygmunt Peter , Högestätt Edward D.
Published: March 2009

Abstract:(+)‐T‐Cadinol is a sesquiterpene with smooth muscle relaxing properties. In the isolated rat aorta, T‐cadinol relaxed contractions induced by 60 mM K+in a concentration‐dependent fashion. The dihydropyridine calcium antagonist nimodipine was approximately 4,000 times more potent than T‐cadinol. While both drugs nearly abolished the K+‐induced contractions, they only partially relaxed contractions induced by phenylephrine. The relaxation induced by T‐cadinol and nimodipine in K+‐contracted aortic rings, was completely reversed by the calcium channel activator Bay K8644. In aortic preparations partially depolarized by 20 mM K+, Bay K8644 induced a concentration‐dependent contraction. Nimodipine shifted the Bay K8644 concentration‐response curve to the right in a parallel manner, consistent with a competitive mode of inhibition. T‐cadinol at concentrations less than 10−3.5M also produced a right‐ward shift of the Bay K8644 concentration‐response curve with a maintained maximum response. However, the highest T‐cadinol concentration used (10−3.5M) significantly reduced the maximum response. In conclusion, although T‐cadinol and nimodipine display marked structural differences, their pharmacological profiles of action have several features in common, suggesting that T‐cadinol is a calcium antagonist, possibly interacting with the dihydropyridine binding sites on the calcium channels.
The Effect of Haloperidol on Ventricular Fibrillation Threshold in Pigs
Authors: Tisdale James E. , Kambe Joseph C. , Chow Moses S. S. , Yeston Neil S.
Published: March 2009

Abstract:Ventricular fibrillation has been observed in association with the administration of haloperidol. This study was designed to determine the effect of intravenous haloperidol on ventricular fibrillation threshold (VFT). VFT's were determined prior to and 15 min. following an intravenous infusion of haloperidol (50 mg administered over 10 min.) in five pigs anaesthetized with α‐chloralose. VFT's were determined using a single stimulus method. Mean arterial pressure (MAP), heart rate (HR), and electrocardiogram (ECG) were monitored continuously. Mean VFT (mA) at baseline and following haloperidol infusion was 50.2 + 4.6 and 65.1 + 12.8, respectively (P < 0.05). Mean MAP (mmHg) at baseline and following haloperidol infusion was 127 + 32 and 107 + 23, respectively (P < 0.05). Haloperidol infusion did not significantly influence mean HR, QRS duration or corrected QT interval. Intravenous haloperidol increases VFT and decreases MAP in pigs. In this model, haloperidol may offer protection against ventricular fibrillation. Further study is required to determine the clinical significance of the antifibrillatory effect of haloperidol.
Aluminofluoride‐ and Epidermal Growth Factor‐Stimulated DNA Synthesis in MOB 3‐4‐F2 Cells
Authors: Kawase Tomoyuki , Orikasa Michiaki , Suzuki Akitoshi
Published: March 2009

Abstract:In attempt to study the mechanism of F−‐induced, osteoblast‐mediated bone formation, we tried to show the characteristics of Al‐F complex‐induced mitogenesis in osteoblastic cells. The MOB 3‐4‐F2 cell line, an osteoblast‐like cell line derived from neonatal mouse calyaria, responded to F−(1‐2 mM) combined with Al3+and epidermal growth factor (EGF, 0.01–10. ng/ml) with increased DNA synthesis. Of the several types of Al‐F complexs, A1F4−is thought to act as a mitogenic factor. On the other hand, NaF at high concentrations (>2 mM) markedly decreased cell viability. The AlF4−‐stimulated DNA synthesis at least with a delay of 48 hr, while EGF stimulated DNA synthesis within a few hours (4‐6 hr). Both 1‐(5‐isoquinolinesulfonyl)‐2‐methylpiperazine dihydrochloride (H‐7) and staurosporine, inhibitors of protein kinase C (PKC), further enhanced DNA synthesis in AlF4−‐treated cells, whereas 12‐O‐tetradecanoyl‐13‐acetate (TPA), an activator of PKC, decreased the DNA synthesis. In EGF‐treated cells, staurosporine and TPA, but not H‐7, decreased DNA synthesis. In addition, indomethacin, an inhibitor of cyclooxygenase, partly inhibited the EGF‐induced mitogenesis, which, however, was restored by addition of PGE2. AlF4−as well as EGF, stimulated the release of arachidonic acid and its metabolites. Indomethacin failed to inhibit the AlF4−‐induced mitogenesis. Thus, the mitogenic response of MOB 3‐4‐F2 cells to F−in the presence of Al3+had the following characteristics: (1) it was effective over a narrow range, (2) it had a slow onset, (3) included a PKC‐sensitive mechanism and (4) a PG(E2)‐independent mechanism. In contrast, a wide range of EGF concentrations rapidly stimulated DNA synthesis by a PKC‐sensitive, PG(E2)‐dependent mechanism in these cells.
Comparative Effects of β‐Adrenoceptor Partial Agonists on
Authors: Atrium Isolated Rat , Vigholt‐Sarensen Else , Påby Lotte , Halliday Sharon E. , Snow H. M.
Published: March 2009

Abstract:The chronotropic effect of three β‐1‐adrenoceptor partial agonists prenalterol, xamoterol and epanolol has been compared on the right atria of the rat in order to evaluate their intrinsic activity and to place them in rank order of effectiveness. The results show that prenalterol, xamoterol and epanolol are all partial agonists. The intrinsic activities relative to that of isoprenaline are 0.84 for prenalterol, 0.59 for xamoterol and 0.29 for epanolol. This rank order of intrinsic activities should remain the same in different species and in man. Both atenolol and propranolol reversed the chronotropic effects of the three agonists. The KBof the two blockers was similar against prenalterol and xamoterol, which indicates that the two partial agonists are probably competing for the same population of receptors. The EC50 is twice as large than KBfor xamoterol, which is consistent with isoprenaline working through both β‐1‐ and β‐2‐ receptors and xamoterol finds it more difficult to block the β‐2‐receptors.