bluuebunny/crossref_metadata_2025 huggingface dataset:
Accumulation in Murine Amniotic Fluid of Halothane and its Metabolites
Authors: Danielsson Bengt R. G. , Ghantous Hanan , Dencker Lennart
Published: July 2010

Abstract: The distribution of radioactivity in pregnant mice was registered at 0, 1, 4, and 24 hrs after a 10 min. period of inhalation of 14C‐halothane. Autoradiographic methods were used to allow to distinguish between the distribution of volatile (non‐metabolized) halothane, water‐soluble metabolites, and firmly tissue‐bound metabolites. While volatile radioactivity was seen predominantly at short survival intervals, e.g. in body fat, blood, brain and liver, metabolites accumulated with time. Peak values occurred at 4 hrs in most organs (measured with liquid scintillation as well). The most remarkable findings were the high concentrations of radioactivity in amniotic fluid (and the ocular fluids of adults) with peak values at 4 hrs and rather high concentrations still prevailing at 24 hrs after inhalation. It is assumed that this activity represents only partly volaile halothane and mostly non‐volatile metabolites. High activity of metabolites was seen in the neuroepithelium of the embryo in early gestation. Firmly tissue‐bound metabolites, still remaining after washing the tissues with trichloroacetic acid and organic solvents, were found in the nasal mucosa, trachea and bronchial tree and in (presumably centrilobular) zones of the liver of adults after inhalation and 5‐day old mice after intraperitoneal injection, indicating the formation of reactive metabolites in these organs. Firmly tissue‐bound activity was not observed in the corresponding foetal organs.
Effect of Lipophilicity of Substituted Benzamides on the Dopaminergic Effects in Vivo and in Vitro
Authors: Hall Häkan , Ögren Sven Ove , Florvall Lennart
Published: July 2010

Abstract: The antidopaminergic potencies of some new substituted benzamides related to remoxipride have been studied in the rat using in vitro (3H‐spiperone binding) and in vivo techniques (antagonism of apomorphine induced stereotypies). The lipophilicities of the different benzamides were calculated by the addition of the lipophilic contribution (π value) of the added substituent. It was found that the in vivo potencies of the compounds were not direct proportional to the in vitro potencies. The discrepancies in the potencies in vitro and in vivo (expressed as the ratio) are correlated to the calculated lipophilicities. Certain substituents in the benzene nucleus affect this in vitro‐in vivo ratio more than could be expected from the change in lipophilicity caused by the substituent. The type of side chain is also of great importance. The reasons for the discrepancies between in vitro and in vivo antidopaminergic potencies of the studied substituted benzamides are discussed.
Solubility of Copper and Zinc Containing Proteins before and after 2‐Mercaptoethanol Treatment of Liver Samples from Normal and from Chronically Copper Poisoned Sheep
Authors: Hussein Kamal S. M. , Frank A. , Jones B.‐E. V. , Edqvist L.‐E.
Published: July 2010

Abstract: The distribution between cytosol and pellet of Cu‐ and Zn‐containing proteins was studies in livers from normal sheep and sheep with chronic copper poisoning (CCP). It was found that the relative amount of soluble Cu‐ and Zn‐containing proteins was lower in liver homogenates from CCP sheep than in homogenates from normal sheep. Treatment of homogenate from the livers with 2‐mercaptoethanol (ME) increased the solubility of Cu‐ and Zn‐containing proteins, especially in CCP sheep. Oxidation of the liver homogenates from normal sheep with air oxygen gave a decrease in the relative amount of soluble Cu‐containing proteins and an increase in Zn‐containing proteins present in the cytosol. It is proposed that oxidation in vivo of Cu and/or the metal‐binding protein causes the observed decrease in soluble Cu‐ and Zn‐containing proteins seen in CCP sheep.
Chapter 7: MULTISTAGE SKIN CARCINOGENESIS: A USEFUL MODEL FOR THE STUDY OF THE CHEMOPREVENTION OF CANCER
Authors: Slaga Thomas J.
Published: July 2010

Abstract: Skin carcinogenesis can be operationally and mechanistically divided into at least three stages; tumor initiation, stage I and stage II of promotion. Current information suggests that reactive intermediates of skin tumor initiators are mutagenic and bind convalently to DNA of epidermal stem cells (dark basal keratinocytes) leading to some irreversible alteration in the differentiation capacity of these cells. Inhibitors of skin tumor initiation by polycyclic aromatic hydrocarbons (PAH) decrease the level of the PAH diol‐epoxide bound to specific DNA adducts. The tumor promoters have been shown to have many cellular and biochemical effects in the skin. Recent data suggests that free radicals may be important in skin tumor promotion. The first stage of promotion is partially irreversible and can be accomplished by a single treatment of a tumor promoter such as TPA or by non‐promoting agents such as 4‐O‐methyl‐TPA, calcium ionophore A23187, and hydrogen peroxide, as well as wounding. These agents increase the number of dark basal keratinocytes, which suggest that these cells are important in the first stage of promotion. Prostaglandin was found to specifically enhance stage I of promotion whereas the protease inhibitor tosyl phenylalanine chloromethylketone (TPCK) specially inhibited stage I of promotion and the TPA‐induced dark basal keratinocytes. The second stage of promotion is initially reversible but later becomes irreversible. The weak promoting agent mezerein is an effective stage II promoter. Polyamines and epidermal cell proliferation appear to be important events in stage II of promotion. Putrescine was found to specifically enhance stage II, whereas retinoic acid (RA), diflouromethylornithine (DFMO), and butylated hydroxyanisole (BHA) specially inhibited stage II of promotion and the mezerein‐induced polyamine levels. Floucinolone acetonide (FA) was found to inhibit both stages but was more effective in counteracting stage I of promotion. Although, TPA can cause a decrease in the number of glucocorticoid receptors during promotion, FA can effectively prevent this loss. Recent data suggest that skin tumor promotion can be effectively inhibited by a combination of stage I and II inhibitors. Furthermore, skin carcinogenesis can be counteracted by a combination of low and nontoxic doses of BHA, TPCK, DFMO and vitamin E.
Chapter 9: CO‐CARCINOGENS OF THE INITIATION‐(OR TUMOR)PROMOTER TYPE AS ENVIRONMENTAL RISK FACTORS OF CANCER IN MAN, EXPERIMENTAL ANALYSIS OF AN ETIOLOGIC MODEL SITUATION OF LIFE STYLE CANCER AND CURRENT PROBLEMS OF ASSESSMENT OF CANCER RISK IN MULTIFACTORIAL CARCINOGENESIS
Authors: Hecker Erich
Published: July 2010

Abstract: The identification of so‐called co‐carcinogens i.e. “per se essentially non‐carcinogenic amplifiers” of carcinogenesis — especially promoters of 1nitiation(or tumors) — as a new, non‐classical group of risk factors has added a new dimension to the etiology of cancer in man. Indeed, in real human life, multifactorial causation of cancer may be considered the rule and classical unifactorial causation the exception. This comprehensive and current concept of the etiology of cancer in man and certain prototype experimental models of multifactorial carcinogenesis allow for proposals of a standardized terminology which may be adequate for common use in both, experimental and epidemiological oncology. On the background of a recent experimental analysis of life style esophageal cancer the current situation regarding the scientific basis of classification and grading of carcinogenic risk factors will be reviewed. It may be helpful in legislation aiming at more environmental safety.
Changes in the lipoprotein profile during antihypertensive therapy
Authors: Helgeland Anders , Leren Paul , Kjeldsen Sverre , Eide Ivar , Foss Olav Per
Published: July 2010

Abstract: In the Oslo study serum lipids have been studied during treatment with some of the most frequently used antihypertensive drugs.

Hydrochlorothiazide induced no significant changes. However, those patients with the most marked increase in uric acid showed an increase of serum ti iglycerides. Total cholesterol was unchanged in these men.

The β‐adrenoceptorblocking drugs propranolol, aterolol and oxprenolol caused a reduction of HDL cholesterol and an increase of total triglycerides. Tolal cholesterol remained unchanged. Pindolol induced no significant lipoprotein changes.

Prazosin reduced total cholesterol and total triglycerides. HDL. cholesterol remained unchanged. LDL + VLDL cholesterol was reduced.
Influence of Injectable Anaesthetic Combinations on Blood Gas Tensions and Acid–Base Status in Laboratory Rats
Authors: Svendsen P. , Carter A. M.
Published: July 2010

Abstract: Outbred Mol: SPRD rats were maintained in surgical anaesthesia for two hours by using five different drug combinations: 1) pentobarbitone, 2) ketamine +diazepam, 3) ketamine + pentobarbitone, 4) atropine + diazepam + fentanyl + fluanisone, 5) atropine+ etorphine + acepromazine. Respiratory rate, arterial O2 and CO2 tensions, arterial pH, base excess, mean arterial blood pressure and heart rate were recorded at set intervals from 30 to 120 min. from the initiation of anaesthesia. Atropine + diazepam + fentanyl + fluanisone caused no disturbance of acid–base balance, whereas the other drug combinations induced moderate to severe acidosis. Arterial blood pressure was reduced by all methods. Pentobarbitone and regimens including ketamine reduced heart rate, whereas combinations with etorphine and fentanyl caused a rise in heart rate.
11–Deoxycortisol Induces Hepatic Tryptophan Oxygenase in Rats
Authors: Gjerde Hallvard , Gadeholt Grim , Olsen Harald , Mørland Jørg , Norman Nils
Published: July 2010

Abstract: 11–Deoxycortisol (cortexolone) has previously been used as a glucocorticoid antagonist in vitro and in adrenalectomized rats. Antiglucocorticoid properties of 11–deoxycortisol in intact rats were examined by studying the effect of 11–deoxycortisol on the induction of hepatic tryptophan oxygenase (TO) by corticosterone. No antiglucocorticoid effect was observed. When 11–deoxycortisol was injected into rats, the TO activity increased. This was probably mainly caused by an elevation of the serum corticosterone level. The induction of TO by 11–deoxycortisol was inhibited by metyrapone. However, 11–deoxycortisol (100 mg/ kg) was still not a glucocorticoid antagonist even in presence of metyrapone
Conversely Exposure–related Effects between Atmospheric m–Xylene Concentrations and Human Body Sense of Balance
Authors: Savolainen Kai , Riihimäki Vesa , Muona Outi , Kekoni Jouni , Luukkonen Rirva , Laine Arto
Published: July 2010

Abstract: Effects of fixed and fluctuating concentrations of m–xylene in air were studied on human psychophysiological functions. Nine healthy male volunteers were exposed to m–xylene 4 hrs a day, 3 hrs in the morning and 1 hr in the afternoon, with a 40 min. break in between. The subjects were sedentary or exercised at 100 W for 10 min at the beginning of each session in the chamber. The m–xylene concentrations in the air were fixed (8.2 μmol/1; 870 mg/m3) or fluctuated with peaks (5.2–16.4 μmol/1; 550–1740 mg/m3) but the TWA (8 hrs) concentration of m–xylene was always 4.1 μmol/1 (435 mg/m3). The two control days, with and without exercise, were similar to the exposure days, but without exposure. Reaction times were measured with a device in which subjects responded to visual and auditory stimuli. Body sway was measured with the subjects' eyes open and closed with a strain gauge transducer platform. Changes in reaction times did not correlate with m–xylene concentrations in the air. Changes of average and maximal body sway were, however, consistently negatively correlated with the intensity of the atmospheric exposure to m–xylene at the beginning of each session in the chamber. Physical exercise combined with exposure to m–xylene improved rather than impaired body sway
Interaction of Certain Metal Ions with Aryl Hydrocarbon Hydroxylase of Rat Lung Microsomes
Authors: Asokan Parthasarathy , Das Mukul , Dixit Rakesh , Mukhtar Hasan
Published: July 2010

Abstract: The effect of varying concentrations of cadmium, copper, zinc, and selenite on the ativity of aryl hydrocarbon hydroxylase (AHH) of rat lungs was studied in vitro. All the metals resulted in a strong inhibition of enzyme activity. Copper and zinc were more inhibitory to rat lung AHH than cadmium and selenite. There was an additive inhibition of AHH activity when copper or zinc was added in the presence of cadmium. EDTA or glutathione exerted a protective effect on cadmium–induced inhibition of AHH activity. Prior incubation of the microsomes with N–ethylmaleimide, a thiol–blocking agent, had no effect on the inhibition of AHH activity caused by cadmium. Addition of cadmium along with zinc–thionein resulted in increased inhibition of rat lung AHH
Effects of Dipyridamole on the Glyceryl–trinitrate–induced Inhibition of Coronary Artery Muscle Tone and Platelet Aggregation in Relation to Cyclic Nucleotide Metabolism
Authors: Ahlner J. , Andersson R. G. G. , Axelsson K. L. , Bunnfors I. , Wallentin L.
Published: July 2010

Abstract: The effects of glyceryl–trinitrate (GTN) and dipyridamole (DIP) on relaxation of bovine coronary arteries and on inhibition of aggregation of human platelets have been studied in vitro with special reference to the cyclic GMP (cGMP) system. GTN had a dose–dependent relaxant effect on bovine coronary arteries, and at a high concentration (10–5 M) it had an inhibiting effect on platelet aggregation. The effects were associated with an increase in the cGMP levels of the tissues. DIP (5 × 10–7 M respectively 5 × 10–6 M) potentiated the coronary artery relaxation induced by GTN (10–8 M) and the inhibition of platelet aggregation caused by GTN in the concentrations 10–7–10–4 M. The potentiation was associated with higher levels of cGMP than those produced by GTN alone, at least in bovine coronary arteries. However, at a concentration of 10–4 M, GTN, in combination with DIP, caused a significant fall in the cGMP level compared to GTN alone. GTN and DIP were not found to significantly increase the cAMP levels in the concentrations tested. DIP was shown to inhibit phosphodiesterase (PDE) from both platelets and bovine coronary arteries. This might be one of the possible mechanisms that can explain the above mentioned potentiation. It is suggested that the combination of DIP+GTN may be of some clinical importance since the potentiating effects were seen at concentrations comparable to the therapeutic plasma concentration for the respective drugs
Single Intravenous and Oral Doses of Fenflumizole: Pharmacokinetics and Effects on Prostanoid Formation
Authors: Vinge Ellen , Arnold Elisabeth , Rasmussen Søren N. , Midskov Carsten
Published: July 2010

Abstract: Fenflumizole is a substituted triaryl–imidazole with anti–inflammatory activity. Its disposition in man was studied after single intravenous and oral doses to 8 healthy male volunteers. Formation of the prostanoids thromboxane B2(TXB2) and 6–keto–prostaglandin F1α(6–k–PGF1α) in clotting blood was studied concomitantly. The pharmacokinetics after intravenous doses (0.1 mg/kg) could be fitted to a three compartment model and the half–lives (t1/2) corresponding to the three phases were 2 min., 1 hour and 15 hours, respectively. The volume of distribution was 386 1 and the plasma clearance 0.5 1 per min. Oral doses (0.5 mg/kg) were rapidly absorbed (t1/2= 0.2 hr) and the following elimination from plasma had two phases with half–lives of 1 hour and 14 hours. Bioavailability was 50% due to a pronounced first–pass effect. The two metabolites mono– and didemethylfenflumizole were detected after both oral and intravenous doses and their maximum plasma concentrations occurred after 1–2 hours irrespective of the administration route. A concentration dependent depression of prostanoid formation was seen, the IC50 for TXB2 and 6–k–PGF1αbeing 19 and 53 ng/ml respectively
Autoradiography of l–Methyl–4–phenyl–l,2,3,6–tetrahydropyridine (MPTP): Uptake in the Monoaminergic Pathways and in Melanin Containing Tissues
Authors: Lydén Annika , Bondesson Ulf , Larsson Bengt S. , Lindquist Nils Gunnar , Olsson Lars‐Inge
Published: July 2010

Abstract: A recently discovered neurotoxic compound, l–methyl–4–phenyl–l,2,3,6–tetrahydropyridine, has been found to cause a parkinsonian–like syndrome in man and monkey, but not in laboratory animals such as rat, mouse and guinea pig. MPTP seems to selectively destroy the melanin containing dopaminergic cells in pars compacta of substantia nigra. Lower mammalian species do not have melanin in these cells, which indicates that the presence of neuromelanin may be of importance for the development of MPTP–induced lesions. By means of whole–body autoradiography of 3H–MPTP in mice, accumulation and retention was observed in the dopaminergic pathways, in locus caeruleus and in structures in the medulla oblongata and spinal cord. A high uptake was also seen in melanin–containing tissues such as in the eyes of pigmented mice. MPTP has earlier been found to have high affinity in vitro for dopamine melanin, which is similar to the pigment in substantia nigra. The typical features of the MPTP–induced neurotoxicity with destruction of pigmented nerve cells and development of parkinsonism may be due to accumulation and retention of MPTP and its metabolites in these cells. In species with pigmented nerve cells, such as man and monkey, the accumulation may be much more pronounced because of the melanin affinity of MPTP and its metabolites
Inhibition by Methylglyoxal bis(guanylhydrazone) of Drug Oxidation Reactions Catalyzed by Mouse Liver Microsomes in Vivo and in Vitro
Authors: Kaipainen Pekka M. , Karvonen Eija H. , Pösö Hannu J.
Published: July 2010

Abstract: The activity of coumarin 7–hydroxylase (coumarin 7–hydroxylation) was inhibited in B6 mouse liver after a single injection of methylglyoxal bis(guanylhydrazone (MGBG). The decrease in the activity in vivo was greatest (70%) one day after the drug injection and the hydroxylase activity in microsomal fraction prepared from livers of MGBG–treated B6 mice was still 25% decreased 5 days after the drug. The amount of cytochrome P–450 also was decreased in MGBG–treated livers with the same time–dependency as the inhibition of coumarin 7–hydroxylation. MGBG and its close derivative 1,1′–((methylethanediylidene)dinilrilo)bis(3–aminoguaniidine) (MBAG) inhibited the activity in vitro of coumarin 7–hydroxylase, benzo(a)pyrene hydroxylase and 7–ethoxy 0–de–ethylase when microsomes were prepared from livers of untreated B6 mice. In every case MBAG was a better inhibitor than MGBG in vitro. The in vitro inhibition of MGBG of several drug metabolizing enzymes was not reversed when microsomes were preincubated with 1 mM putrescine, spermidine or spermine. These results suggest that the anti–cancer drug, MGBG, has a severe effect(s) on the drug metabolizing system at concentrations reached during the treatment of patients with MGBG
Distribution of 64Cu in Foetal and Adult Tissues in Mice: Influence of Sodium Diethyldithiocarbamate Treatment
Authors: Jasim Suhair , Danielsson Bengt R. G. , Tjälve Hans , Dencker Lennart
Published: July 2010

Abstract: 64Cu (as 64CuCl2) was given intravenously to male C57BL mice and to pregnant C57BL mice at various stages of gestation. The disposition of the 64Cu in the adult animals and in the foetuses was studied by autoradiography and δ spectrometry. The effects of treatments with diethyldithiocarbamate (DEDTC) on the disposition of the 64Cu in the animals were also examined. In addition, the ability of Cu to affect chondrogenesis was studied in an embryonic limb bud culture system. The results showed a strong uptake of 66Cu in the liver of the adult animals at all intervals (5 min.–24 hrs). At short survival intervals, there was also an uptake in the kidney cortex, the gastrointestinal mucosa, the adrenal, the pancreas, and the erythrocytes. Exposure to Cu may cause liver and kidney injuries, which may be related to the strong accumulation in these organs. 64Cu passed the placenta to the foetuses at all stages of gestation, although this occurred at a relatively slow rate. Within the foetuses the highest concentrations were found in the liver. Cu was observed to be toxic in the chick limb bud mesenchymal spot culture system although at relatively high concentrations. Foetal malformations and embryotoxicity may therefore be interpreted as a result of direct action of Cu on embryonic structures, although placental and/or maternal influence cannot be excluded. Pre– or posttreatments of the animals with DEDTC, which is a chelating agent, caused a very marked increase in the concentration of 64Cu in most tissues of the adult animals and also an increased foetal uptake of the metal. The highest relative increase was found in the brains of both the adults and the foetuses. The complex between DEDTC and Cu is lipophilic, and a facilitated penetration of the complex through the cellular membranes probably explains the increased uptake of the 64Cu in the tissues. DEDTC can induce noxious effects on the central nervous system and on foetal development. It is possible that these effects are mediated via an interference in the metabolism of metals, including Cu
Sensitivity of Preimplantation Mouse Embryos to Abrin
Authors: Storeng Ritsa
Published: July 2010

Abstract: The effect of the plant toxin abrin on preimplantation mouse embryos in vitro was studied. Two–cell embryos from C57BL/6J or B6CBA/Fl/Bom ♀ × B6CBA/Fl/Bom ♂ mice were exposed to abrin for 72 hrs in vitro, in medium containing abrin in concentrations ranging from 0.1 to 10,000 pg/ml. Two–cell mouse embryos were also exposed to corresponding concentrations of ricin in vitro. The effect of abrin was evaluated by daily morphological observation of the embryos up to the blastocyst stage and by measuring DNA, RNA and protein synthesis by radioactive precursor incorporation. The effect of ricin was evaluated by morphological observation of the embryos up to the blastocyst stage. The results showed that 2–cell mouse embryos were highly sensitive to abrin, 1 pg/ml being the lowest concentration of the toxin that significantly inhibited the development of 2–cell embryos to the blastocyst stage. With ricin statistically significant inhibition of blastocyst formation was obtained at a concentration of 10 pg/ml. The ID50 for abrin was calculated to be 24 pg/ml and for ricin 47 pg/ml. A dose–dependent lag period was observed before the effect of abrin or ricin on the formation of blastocysts became evident. Incorporation of 3H–thymidine, 3H–uridine and 14C–leucine into DNA, RNA and protein, respectively, was also inhibited by abrin after different time intervals in culture
The Distribution of 14C–Chloramphenicol in the Japanese Quail (Coturnix coturnix japonica)
Authors: Appelgren L.‐E. , Biessmann A. , Martin K. , Salemi M. A. , Wiese B.
Published: July 2010

Abstract: The distribution of 14C–labelled chloramphenicol after oral and intravenous administration to egg laying Japanese quail was studied by whole–body autoradiography. In the liver, kidneys, gizzard, intestinal contents (bile) and oviduct, the 14C–concentration was higher than that of the blood short time after injection and remained higher than the blood up to 4 days. From 4 hrs, the concentration of 14C in the egg yolks was higher than that of the blood and from 24 hrs the radioactivity in the albumen of the eggs in the oviduct was also higher than that of the blood. The peak concentration in the egg yolk was found in the second egg laid 2–4 days after administration of 14C–chloramphenicol. In the albumen the maximum concentration was found in the first laid egg 24–48 hrs after administration. In the egg yolks, about 30% of the radioactivity represented unchanged chloramphenicol up to 5 days after administration. It was also shown that about 5% of the injected 14C–chloramphenicol was exhaled as 14CO2 during the first 12 hrs and about 37% of the dose was excreted in the combined faeces and urine during the same period of time
Differences in the Haemorrhagic Toxicity of Aspirin between Rats and Mice
Authors: Takahashi Osamu , Hiraga Kogo
Published: July 2010

Rats and mice were fed a diet containing aspirin at levels of 0, 0.3, 0.6 and 1.2% for 1 and 4 weeks. Haemorrhagic death and/or haemorrhagic anaemia occurred in rats in a dose‐dependent manner. Prothrombin and kaolin‐activated partial thromboplastin time indices were also decreased depending on the daily doses. However, no conspicuous haemorrhagic signs were found in mice given aspirin. These results suggest marked differences in haemorrhagic effects of aspirin between rats and mice. From results of supplementary experiments with two metabolites of aspirin, salicylic acid and gentisic acid, and from the fact of close relationship between hepatic concentration of salicylic acid and haemorrhagic effects of aspirin, it is inferred that salicylic acid may be a precursor for the active metabolite(s) to cause haemorrhage. The mechanism of species differences of aspirin is discussed.
Chlorpromazine Increases the Lowered Response to Antidiuretic Hormone in Rats with Lithium‐induced Diabetes Insipidus
Authors: Kristensen Anne Riise , Hammer Mogens , Christensen Sten
Published: July 2010

The interaction between chlorpromazine (CPZ) and lithium on renal concentrating ability was studied in rats fed a Li‐containing diet for 8 weeks (plasma‐Li 0.6–0.7 mmol/l). CPZ (15 mg/kg daily orally) reduced the polydipsia and increased the ability to concentrate the urine upon water deprivation in rats treated with lithium. CPZ also reduced systolic blood pressure, but had no effect on the glomerular nitration rate or plasma levels of arginine vasopressin (AVP) in hydrated rats treated with lithium. However, CPZ prevented the rise in plasma AVP levels observed in lithium‐polyuric rats in response to dehydration. During anaesthesia CPZ partially restored the impaired anti‐diuretic response to exogenous AVP in rats treated with lithium. CPZ had no influence on plasma‐Li levels in rats treated with lithium. It is suggested that CPZ by unknown mechanisms interferes with the effects of lithium on the water permeability response to AVP.
p,p′‐DDT‐Induced Myoclonus in Mice: The Effect of Enhanced 5‐HT Neurotransmission
Authors: Magnussen Ib
Published: July 2010

The acute behavioural consequences of intragastric p,p′‐DDT in high doses to mice are stimulus sensitive abrupt muscle jerks (myoclonus). The serotonin (5‐HT) precursor 5‐hydroxytryptophan (5‐HTP) ameliorated in contrast to the natural precursor tryptophan, the neurotoxin‐induced myoclonus. The extracerebral decarboxylase inhibitor carbidopa and the selective 5‐HT reuptake inhibitor paroxetine both enhanced the antimyoclonic action of 5‐HTP. The effect was reversed by the 5‐HT receptor blockers cinanserine and methysergide. The data add further evidence to a central serotonergic mechanism involved in p,p′‐DDT induced myoclonus.
Rapid Formation of Reduced Haloperidol in Guinea Pigs Following Haloperidol Administration
Authors: Korpi Esa R. , Costakos Dennis T. , Wyatt Richard Jed
Published: July 2010

Haloperidol, a butyrophenone neuroleptic, is metabolically reduced in man, but not in rat and not in many other experimental animals. Here we present data that describes reductive haloperidol metabolism in guinea pigs in vivo. When haloperidol was injected intraperitoneally to guinea pigs, it was converted to reduced haloperidol so quickly that 1 hr after the injection the concentration of haloperidol was only about one fifth of that of reduced haloperidol. Dopamine metabolism was enhanced in the striatum after the administration of reduced haloperidol, but this enhancement could mostly be explained by oxidation of a small amount of reduced haloperidol back to haloperidol. The molecular mechanisms of haloperidol reduction should be further studied using guinea pigs as a model for human haloperidol metabolism.
Cyclic GMP Affects Redox State and Improves Energy Charge of Ischaemic Langendorff‐perfused Rat Heart
Authors: Laustiola Kai
Published: July 2010

The effects of 8‐bromo cyclic GMP (1 × 10−5M) on the levels of lactate, NAD+, NADH, AMP, ADP, ATP, creatine phosphate (CrP) and creatine were studied in the ischaemic Langendorff‐perfused rat heart. The NAD+/NADH ratio and the energy charge were also calculated. The dependence of the effect of 8‐bromo‐cGMP on substrate availability was also studied by adding pyruvate (5 mM and 10 mM) to the perfusate, and by comparing the changes to those during perfusion with glucose alone. When glucose (11 mM) was used as the only substrate, 8‐bromo‐cGMP administration resulted during ischaemia, in a decrease of the NADH level, and in an increase of the energy charge. When pyruvate (5 mM) was added to the perfusate, 8‐bromo‐cGMP administration resulted in an increase in the NAD+/NADH ratio and in an increase of the energy charge. When the pyruvate concentration was further increased (10 mM), no changes were seen in the beforementioned variables after 8‐bromo‐cGMP administration. It is concluded that the effects of 8‐bromo‐cGMP may be exerted by an enhancement of carbohydrate oxidation.
The Influence of Sustained Release Theophylline Therapy on Free Fatty Acids in Serum
Authors: Walstad R. A. , Myhre K. I. , Wirum Elin , Wessel‐Aas T.
Published: July 2010

The serum concentrations of theophylline, total free fatty acids (FFA) and subgroups were studied in ten healthy volunteers treated with sustained release theophylline twice daily during 9 days. Analyses were performed before and on day 1, 4 and 9 of treatment. Mean theophylline serum levels within the therapeutic range were obtained during the study, ranging from 62 ± 7 to 82 ± 10 umol/1. The mean serum concentrations of total FFA and subgroups increased significantly during treatment, showing the highest levels on day 4. Comparing fasting total FFA concentrations, an increase of 123% and 48% from pretreatment levels were found on day 4 and 9, respectively. The subgroups were influenced to a different degree by theophylline intake. Arachidonic acid (20:4) was not increased, while among the others, saturated FFA increased less than the unsaturated.
Acute Interaction of Halothane and Enflurane with the Metabolism of Ethanol in Isolated Hepatocytes and Liver Cytosol Preparations from the Rat
Authors: Aune Håkon , Normann Per Trygve , Olsen Harald , Nesset Gunnar , Morland Jarg
Published: July 2010

The effects of halothane and enflurane on ethanol (40 mM) oxidation were studied in isolated rat hepatocytes. Anaesthetic (halothane, enflurane and diethyl ether) effect on the activity of alcohol dehydrogenase (ADH) was studied in incubations of cytosol preparations from rat liver. Mean rates of ethanol metabolism ranged from 0.44 to 0.49 μmol ethanol metabolized/mg cell protein/hour in control hepatocytes from fasted and fed animals. These rates were enhanced by 2‐ and 3‐fold in hepatocytes from fed and fasted animals, respectively, when pyruvate (5 mM) was added. Halothane and enflurane both caused dose dependent inhibition of ethanol metabolism (15‐40%) in all hepatocytes without exogenous addition of pyruvate. The inhibitory effect was present also after pyruvate stimulation in hepatocytes from fasted animals, but disappeared in hepatocytes from fed animals when pyruvate was added. The rate of ethanol oxidation by cells from fed rats was enhanced by approximately 40% when the concentration of ethanol was increased from 20 mM to 80 mM. The anaesthetic inhibition of ethanol metabolism was about 20% more pronounced at the higher ethanol concentration compared to the lower concentration when no pyruvate was added. In the presence of pyruvate the effect of anaesthetics was again reversed regardless of ethanol concentration. Halothane (2 mM) and enflurane (2 mM) both caused about 25% inhibition of the ADH‐activity in cytosol preparations while ether (30 mM) caused more than 50% inhibition. No inhibition of hepatocyte uptake of ethanol was caused by any of the three anaesthetics. It was concluded that the volatile anaesthetic agents in addition to their well known membrane effects also seem to be able to interfere directly with the activity of the non‐membrane related enzyme ADH.
Doxazosin Increases Low Density Lipoprotein Receptor Activity
Authors: Leren Trond P.
Published: July 2010

The effect of the α1adrenoreceptor antagonist doxazosin on low density lipoprotein (LDL) receptor activity, has been studied in cultured skin fibroblasts. Doxazosin at a concentration of 10−5M significantly increased the LDL receptor activity. The possible clinical implications of this observation are discussed.
Kinetics of Disopyramide after Intravenous Infusion to Patients with Myocardial Infarction and Heart Failure
Authors: Bonde Jan , Angelo Helle R. , Bødtker Søren , Svendsen Tage Lysbo , Kampmann Jens P.
Published: July 2010

Total body clearance, half‐life and volume of distribution of disopyramide (Norpace, Searle G.D.) was measured during a six to eight hour infusion to steady state in twenty four patients with either congestive heart failure or acute myocardial infarction and compared to eleven patients without these diseases. All patients were given a bolus injection of 150 mg disopyramide followed by a continuous infusion of 18–24 mg per hour. Serum concentration of disopyramide and its main dealkylated metabolite were determined by HPLC. The clearance in patients without myocardial infarction or congestive heart failure was 1.71 ± 0.60 ml/min./kg (X̂ ± S.D.), not significantly different from those who had either myocardial infarction, congestive heart failure or both. Half‐life was 798 min. in patients without heart failure, not significantly different from the values in the other groups. The ratio between disopyramide and its metabolite varied between 3 to 10. Twentysix % of the steady state serum concentrations of disopyramide were outside the recommended therapeutic range (2–5 μg/ml), but no adverse haemodynamic effects were observed in any of the patients. The suggested dosage regimen of disopyramide seems to result in a satisfactory response.
Effect of Toxic Doses of Progesterone on Hepatotoxic Effects of Tetracycline
Authors: Böcker R. , Strobel B. , Hopf G. , Estler C.‐J.
Published: July 2010

The combined effects of high doses of tetracycline and progesterone on parameters indicative for liver function (serum transaminases and urea, serum and liver triglycerides and cholesterol) have been studied in mice. Apart from disturbance of cholesterol metabolism tetracycline‐induced liver dysfunction was not aggravated by progesterone.
On the occasion of the 40th anniversary of Acta pharmacologica et toxicologica, May 5th, 1985
Authors: Bain James A.
Published: July 2010

The first issue of Acta pharmacologica et toxicologica was circulated on May 5th, 1945, the very day on which World War II ended in Denmark. The journal is the official publication medium of the Scandinavian Pharmacological Societies. The societies are also represented by associate editors in the editorial board of Pharmacological Reviews. On the happy occasion of the anniversary, we were pleased to receive the following congratulation address from the editor of Pharmacological Reviews, James A. Bain, Ph.D., past president of the International Union of Pharmacology, and Professor of Pharmacology, School of Medicine Emory University, Atlanta, Georgia 30322, U.S.A.

Jens S. Schou
Diltiazem and Propranolol, Alone and in Combination, on Exercise Performance and Left Ventricular Function in Patients with Stable Effort Angina: A Double‐Blind, Randomized, and Placebo‐Controlled Study
Authors: Schroeder John S. , Hung Joseph , Lamb Irene H. , Connolly Stuart J. , Jutzy Kenneth R. , Goris Michael L.
Published: July 2010

Abstract: Diltiazem and propranolol alone and in combination as antianginal agents were compared with placebo in 12 patients with stable exertional angina at Stanford University Medical Center. The patients performed symptom‐limited, multi‐stage upright bicycle ergometric exercise while undergoing radionuclide angiographic studies every two weeks while being treated with 90 mg of diltiazem four times daily, 60 mg of propranolol four times daily, a combination of 90 mg of diltiazem and 60 mg of propranolol four times daily, and placebo. Diltiazem, propranolol and a combination all significantly increased exercise duration compared to placebo (526 ± 149, 525 ± 115, and 549 ± 129 vs 430 ± 132 sec). Although rate pressure product and heart rate decreased with diltiazem therapy at submaximal workloads, these values were unchanged at peak exercise in contrast to propranolol or the combination of propranolol or diltiazem. Diltiazem decreased the sub‐maximal and maximal degree of exercise‐induced ST segment depression by over 50% compared to placebo (P < 0.01 vs placebo). Diltiazem resulted in a higher exercise left ventricular ejection fraction compared to placebo, propranolol or the combination of diltiazem or propranolol (all less than P < 0.05). Sinus bradycardia or orthostatic hypertension occurred in four patients on the high‐dose combination therapy and required dose reduction. We concluded that high‐dose diltiazem, appeared to be even more effective than moderate‐dose propranolol or the combination of diltiazem and propranolol in improving exercise tolerance, electrocardiographic evidence of myocardial ischaemia and left ventricular function in patients with stable effort angina due to occlusive coronary artery disease.
Stimulation of Hepatic Polyamine Metabolism Following Intraperitoneal Injection of some Dietary Oils
Authors: Osmundsen Harald , Eliassen Knut
Published: July 2010

Abstract: Intraperitoneal injection of partially hydrogenated marine oil into rats is shown to cause marked stimulation of hepatic polyamine metabolism, as characterized by increased activity of ornithine decarboxylase (EC 4.1.1.17), and corresponding increase in tissue levels of putrescine. A maximal effect was observed about 5 hours after injection. An effect on the hepatic activity of S‐adenosyl‐methionine decarboxylase (EC 4.1.1.50) was also observed. Of the various dietary oils examined only partially hydrogenated marine oil gave significant stimulation of polyamine metabolism. A single oral dose of partially hydrogenated marine oil gave a small increase in hepatic ornithine decarboxylase activity.
Metabolism of a Dithiocarbamate Fungicide Thiram to Carbon Disulfide in the Rat and its Hepatotoxic Implications
Authors: Dalvi R. R. , Deoras D. P.
Published: July 2010

Abstract: Thiram, tetramethylthiuram disulfide, is used extensively as an agricultural fungicide whose toxicity is largely dependent on its metabolism. The following experiments were carried out to investigate whether carbon disulfide (CS2) is a metabolic product of microsomal monooxygenase catalyzed metabolism of thiram in rats. Adult male Sprague‐Dawley rats (160–200 g) were given thiram (60 mg/kg, b. wt.) in corn oil by intraperitoneal injection and placed individually in a metabolic apparatus. Concentration of CS2 in the breath was determined by drawing the expired air through a series of traps containing a CS2 complexing agent. Expiration of CS2 was almost complete within 5 hrs following thiram administration. The formation of CS2 from thiram was increased by pretreatment of rats with phenobarbital and decreased by SKF 525‐A. Furthermore, measurement of the activities of hepatic microsomal and serum enzymes at 5 hrs and 24 hrs following thiram treatment indicated that thiram caused significant loss of cytochrome P‐450 and benzphetamine N‐demethylase activity only at 24 hrs interval whereas there was significant elevation of sorbitol dehydrogenase (SDH) and serum glutamic oxalacetic transaminase (SGOT) activity at 5 and 24 hrs after treatment. The data confirm that CS2 is an in vivo metabolite of thiram and may be, in part, responsible for the observed hepatotoxicity.
Importance of the Interaction of Midazolam and Cimetidine
Authors: Salonen M. , Aantaa E. , Aaltonen L. , Kanto J.
Published: July 2010

Abstract: Six healthy volunteers were given in an open study 15 mg of midazolam orally, and a couple of weeks later the same treatment preceeded by 400 mg of cimetidine orally. We followed midazolam serum concentrations and the following pharmacodynamic parameters for five hours: subjective sedation, Maddox wing readings, critical flicker fusion frequency and peak velocity of saccadic eye movements. A statistically significant change was found in Cmax and total AUC between the two sessions. The pharmacodynamic responses differed also clearly from each other suggesting a significant change in midazolam effect even after a single oral dose of cimetidine.
Induction of Rat Hepatic Microsomal Epoxide Hydrolase by Substituted Urea Herbicides
Authors: Schoket Bernadette , Vincze István
Published: July 2010

Abstract: Short‐term effect of eight substituted phenylurea herbicides has been investigated on the induction of rat hepatic microsomal epoxide hydrolase activity using an HPLC method with unlabelled styrene oxide as substrate. Each compound increased epoxide hydrolase activity 1.5–4 times the controls.
Placental Transfer of Benzo(a)pyrene and its Hydrophilic Metabolites in the Guinea Pig
Authors: Kihlström Ingemar
Published: July 2010

Abstract: The placental transfer of benzo(a)pyrene, (BP) and its hydrophilic metabolites, (mBP) have been studied in the guinea pig by a placental perfusion technique during constant infusion of BP to the dam. In connection with stop of infusion, blood samples were withdrawn from intact foetuses remaining in utero via the umbilical vein. The placental transfer rate of BP is faster compared with that of mBP when heparinized blood from adult guinea pigs is used as perfusion media. Transfer rate was essentially the same when heparinized blood from foetuses was used instead of blood from adults. With a dextran solution as perfusion media no transfer of BP or mBP could be seen. With albumin solutions of different concentrations only negligible amounts of BP or mBP penetrated the placenta. The concentration of BP in perfusion plasma was significantly higher than that in the foetal plasma, contrary to the concentration of mBP which is significantly lower in perfusion plasma than in foetal plasma. It is concluded that in late gestation the foetal exposure for mBP is due more to the foetal metabolic conversion of BP than to the foetal exposure of mBP produced by maternal enzymatic activity.
Lithium‐induced Uraemia in Rats: Survival and Renal Function and Morphology after One Year
Authors: Christensen Sten , Ottosen Peter D.
Published: July 2010

Abstract: Chronic renal failure was induced in Wistar rats by administration of a LiCl‐containing (40 mmol/kg) diet from birth until an age of 55–65 weeks. The 55 weeks mortality was 51% in Li‐uraemic rats versus 6% in control rats. In surviving rats the mean plasma Li levels were 0.6–0.7 mmol/l after 16 weeks and 1.0–1.1 mmol/l after 48 weeks. The mean plasma urea level was 14 mmol/l after 16 weeks and 22 mmol/l after 48 weeks of treatment compared with 8 mmol/l in the controls rats. In 55 weeks old Li‐uraemic rats inulin clearance was reduced by 62% and Li clearance by 39%. Thus, fractional Li excretion was increased (from 20 to 34%) in rats with chronic Li‐uraemia. Li‐uraemic rats also had polyuria and failed to concentrate their urine in response to exogenous vasopressin. Systolic and mean arterial blood pressures were not significantly changed in rats with Li‐uraemia. Morphological examinations of the kidneys showed large cortical cysts formed by dilated distal tubules and collecting ducts and widespread interstitial fibrosis. Proximal tubular mass was reduced by 50% and glomerular volume was also significantly reduced. The results indicate that in rats with Li‐induced uraemia renal function and morphology deteriorate during Li‐exposure up to an age of one year, associated with increased mortality.
Effects of Intravenous Radiographic Contrast Media on the Blood Pressure and on Factors of the Contact Activation System in the Rat
Authors: Hoem Nils‐Ove , Briseid Gudrun , Ekelund Sverre , Salvesen Sigbjørn
Published: July 2010

Abstract: Blood pressure (BP), plasma prekallikrein (PK), and the extent of activation of factor XII (XII‐ACT) were studied after the intravenous injection into rats of dextran (Macrodex®), the ionic radiographic contrast substance iodipamide (Biligrafin®), or the non‐ionic contrast substance iohexol (Omnipaque®). After acetone activation plasma kallikrein was assayed as plasminogen activator, BAEe esterase or S‐2302 amidase, and factor XIIa was assayed as kaolin‐activated prekallikrein activator. Dextran induced a strong and lasting hypotension, preceded by significant lowerings in PK and XII‐ACT. Iodipamide induced a rapid and dose dependent BP fall, no change in plasma PK, but a slightly reduced XII‐ACT. Iohexol induced no significant alterations, neither in BP, nor in plasma parameters. Pretreatments of the rats with iodipamide abolished the dextran‐induced reductions in PK and XII‐ACT, and almost blocked the fall in BP. We conclude that the ionic contrast substance iodipamide is capable of blocking dextran shock in the rat by preventing an activation of the contact activating system in plasma.
Phthalate Esters: Effects of Orally Administered Dibutylphthalate on Cytochrome P‐450 Mediated Metabolism in Rat Liver and Lung
Authors: Walseth Frode , Nilsen Odd G.
Published: July 2010

Abstract: Dibutylphthalate (DBP) was administered to male Sprague Dawley rats in oral doses of 0.01, 0.1 and 1.0 mmol/kg for five days. The lower dose was considered relevant to human intake. Additional groups were given a recovery period of four weeks without DBP. DBP significantly increased the liver microsomal concentration of cytochrome P‐450 (48%) at the lowest dose and NADPH‐cytochrome‐c‐reductase activity (28–29%), at the two lower doses. The liver microsomal metabolism of n‐hexane increased to about the same extent at all dosage levels. The main increase was found in the formation of the preneurotoxic metabolite 2‐hexanol. The induction of cytochrome P‐450 and NADPH‐cytochrome‐c‐reductase in liver microsomes did not return to normal after the period of recovery, whereas the metabolism of n‐hexane normalized during the same period of time, indicating that the majority of the induced forms of cytochrome P‐450 were not related to n‐hexane metabolism. No major changes were observed in the liver microsomal metabolism of B(a)P. The only effect found in cytochrome P‐450 related metabolism in lung microsomes was a decrease of the B(a)P metabolism, especially in the formation of the 9,10‐ and 4,5‐diol metabolites at lower dosage levels. It is suggested that DBP and its hydrolyzed products formed in the intestine after oral administration exert the same effect on some specific forms of cytochrome P‐450 in liver and lung. It is concluded that DBP is a moderate to weak inducer of several minor forms of liver microsomal cytochrome P‐450 enzymes in doses which may be relevant to human oral intake.
Effects of N‐Nitrosopyrrolidine and N‐Nitrosoproline on the Incorporation of 3H‐Thymidine into the DNA of Various Organs of the Mouse: Tissue Specificity and Effects of Ethanol Consumption
Authors: Hellman Björn , Tjälve Hans
Published: July 2010

Abstract: The effects of the carcinogenic N‐nitrosamine N‐nitrosopyrrolidine (NPYR) and the non‐carcinogenic N‐nitrosamino acid N‐nitrosoproline (NPRO) on 3H‐thymidine incorporation into DNA were evaluated in various organs of male C57BL mice. The N‐nitroso compounds were given intraperitoneally 24 hrs before sacrifice in equimolar amounts (148 μmol/kg b. wt.). Two hours before the mice were killed, they were given an intraperitoneal injection of 3H‐thymidine. NPYR, but not NPRO, induced a tissue‐specific inhibition of 3H‐thymidine incorporation into DNA. The inhibition occurred only in organs reported to be involved in the biotransformation of NPYR, i.e., the liver, lung, and nasal mucosa. Daily oral consumption of ethanol (1.8 ml 30% ethanol for 30 days) had no effects in itself on 3H‐thymidine incorporation, but resulted in an enhancement of the inhibitory action of NPYR in the lung and nasal mucosa.