bluuebunny/crossref_metadata_2025 huggingface dataset:
Availability of Data on Humans Potentially Exposed to Suspected Carcinogens in the Danish Working Environment
Authors: Hansen Johnni , Schneider Thomas , Olsen Jørgen H , Laursen Bjarne
Published: March 2009

For the majority of suspected carcinogens only little or no human evidence exists, and in general ongoing epidemiologic studies fail to address this fast growing group of chemicals. A survey based on a Danish occupational surveillance system concerning data on present and historical import, production and use of the 167 chemicals evaluated by the International Agency for Research on Cancer as possible or probable carcinogens, shows that about 110 of these chemicals are on the market in Denmark at present. Only 32 are used in industry in relatively large quantities. For some of these chemicals it is possible to identify clusters of companies, including historical cohorts of potentially exposed workers. Measurements of airborne pollutants are available for some few of the suspected carcinogens, indicating decreasing time trends and various levels in different industries. In spite of some limitations, this information on potential exposure has on ad hoc basis been linked to an existing cancer registry based occupational surveillance system, and various studies based on the total body of data are on‐going, as a preliminary approach to give at least some human evidence to some widespread animal carcinogens.
Legislation by the European Community on Carcinogens
Authors: Skov Torsten , Hermind Benét , Lynge Elsebeth
Published: March 2009

A brief overview is given of the legislation in the European Community concerning the classification and labelling, marketing and use, occupational exposure, etc. of carcinogenic agents. This includes data on the regulation of 739 agents which have been evaluated for carcinogenicity by the International Agency for Research on Cancer and/or the European Community. These data have been collected in a computerized data base. Although no comprehensive evaluation of the legislation is attempted, it is suggested that a number of carcinogenic agents still need attention, and that the labelling requirements should be supplemented with more restrictive legislation.
Regulating Carcinogenic Risks from Foodstuffs: Present Danish Approaches
Authors: Knudsen Ib
Published: March 2009

The aim of the present Danish regulatory toxicological efforts is to identify and eliminate human carcinogens introduced in the human food supply directly or indirectly through the activity of man. The efforts are directed towards food additives, contaminants and food itself, both individual food items and dietary habits. The overall goal is to bring down the incidence of cancer. The scientific rationale for achieving this goal is discussed based upon recent knowledge. It is suggested that more scientific efforts should be directed towards determining the qualitative and quantitative role of the natural food constituents in human cancer causation.
Some Biochemical and Pathophysiological Aspects of Long‐Term Elevation of Brain Ornithine Concentrations
Authors: Daune‐Anglard Geneviève , Bonaventure Nicole , Seiler Nikolaus
Published: March 2009

Mice and chicken were given 5‐fluoromethylornithine (5FMOrn), a selective inactivator of ornithine aminotransferase (OAT) over extended periods of time. This treatment allowed us to maintain elevated concentrations of ornithine in all tissues. Since gyrate atrophy, an autosomal recessive human disease, is characterized by the absence of OAT, special emphasis was put on the study of the visual system. Ophthalmoscopic and histologic examinations of the eye as well as electroretinograms and locomotor behaviour demonstrated an unimpaired visual system and brain. No toxic effects were observable in the treated mice. Likewise, chick embryo development was normal in spite of highly elevated brain and tissue ornithine concentrations. A likely explanation for the absence of toxic effects of 5FMOrn treatment, disregarding the non‐toxicity of ornithine, is the fact that 10‐20% of tissue OAT is refractory to inactivation by 5FMOrn. This residual activity may be sufficient to maintain vital functions.
Reverse Cholesterol Transport in the Rat: Influence of Short‐Term D‐myo‐inositol‐1,2,6 Trisphosphate (PP56) Infusion
Authors: Wang Wen‐Qi , Wang Xiang‐Dong , Gustafson Anders
Published: March 2009

D‐myo‐inositol‐1,2,6 trisphosphate (PP56) was infused in rats for 3 hr at a rate of 30.28 μM/hr/kg body weight. The cholesterol content in plasma, erythrocytes, the aorta, and the liver was monitored before and at the end of the infusion and at 1 and 21 hr after the infusion. We found that the aortic total and free cholesterol content was reduced after the infusion and continuously until the end of the experiment (by 27% each after 21 hr P < 0.05, P < 0.01, respectively). Erythrocyte cholesterol was increased by 6.6% (P < 0.05) at the end of the infusion and 9.5% (P < 0.01) at the end of the experiment, while plasma and high‐density lipoprotein cholesterol did not change significantly. Free cholesterol in the liver after infusion was decreased by 27% (P < 0.001) and cholesterol ester increased by 97% (P < 0.05) and did not return to the preinfusion level. Short‐term PP56 infusion in the rat apparently infuences cholesterol transport in a way which would suggest a promoted reverse cholesterol transport. Since the lipid values did not return to the preinfusion level, a long‐term study is needed to elucidate in more detail the influence of PP56 on cholesterol metabolism in vivo.
Tricyclic Antidepressants Inhibit Opioid Receptor Binding in Human Brain and Hepatic Morphine Glucuronidation
Authors: Wahlström Agneta , Lenhammar Lena , Ask Birgitta , Rane Anders
Published: March 2009

Abstract:The opioid receptor binding in the human thalamic area was studied with U‐69593 and naloxone as ligands for the kappa and mu receptors, respectively. The binding was inhibited by various tricyclic antidepressants including amitriptyline, nortriptyline, clomipramine and fluoxetine. The antidepressants tested had a slight selectivity for the kappa receptor type. The IC50‐values for all tricyclic antidepressants tested were in the 10‐6M concentration range. Morphine and tricyclic antidepressants are substrates of a liver microsomal uridine diphosphate glucuronyl transferase (UDPGT). The interaction of the tricyclic antidepressants with morphine glucuronidation was investigated in human liver microsomal preparations. All drugs inhibited the morphine UDPGT. In Dixon plots inhibition of the formation of morphine‐3‐glucuronide and morphine‐6‐glucuronide was non‐competitive for nortriptyline, and competitive or mixed for amitriptyline and clomipramine. Lubrol PX activated the morphine‐UDPGT four to five times. The degree of activation of the enzyme(s) was unaltered in presence of the inhibiting drugs. The inhibition was also observed at a tricyclic antidepressant/morphine concentration ratio close to that achieved in plasma from patients treated with these drugs.
Effect of Wall Tension on DNA and Protein Synthesis in Bovine Mesenteric Arteries in Vitro
Authors: Chen Yun , Mirtensson Lena G. E. , Axelsson Krister L. , Lundholm Lennart , Arnqvist Hans J.
Published: March 2009

Abstract: The aim of this investigation was to study the effect of wall tension and calcium antagonists on DNA and protein synthesis in bovine mesenteric arteries in vitro. The wall tension of the bovine mesenteric arteries was raised by stretching the vessel wall perpendicular to the length axis of the vessel. DNA and protein synthesis were determined by measuring incorporation of 3H‐thymidine into DNA and incorporation of 14C‐leucine into protein respectively. Elevating the wall tension from 0.05 N to 0.5 N significantly increased 3H‐thymidine incorporation and 14C‐leucine incorporation after an incubation period of 3 hr. Stretch had no effect on the distribution of 3H‐thymidine. The distribution of 14C‐leucine was increased by stretch in regular medium and to a less extent in calcium‐free medium, which suggest that stretch stimulates the membrane transport of 14C‐leucine. When the tension was increased from 0.05 N to 0.5 N for 10 min. before the incubation with 3H‐thymidine, no effect was found. One μM nifedipine or felodipine inhibited the increase in 3H‐thymidine incorporation caused by stretching, while no effect was found on 14C‐leucine incorporation. In calcium‐free medium, stretch‐induced DNA synthesis was completely abolished. 14C‐Leucine incorporation was impaired in calcium‐free medium but the stretch‐induced increse still remained. The results suggest that mechanical force may play an important role in DNA synthesis and protein metabolism of vascular smooth muscle.
Individual, Culture‐Specific Alterations in the Human Endothelial Glutathione System: Relationships to Oxidant Toxicity
Authors: Tu Ba , Wallin Alf , Moldéus Peter , Cotgreave Ian A.
Published: March 2009

Abstract: In this comunication we report on the effects of serial passage of human umbilical vein endothelial cells on the levels of GSH and activities of selenium‐dependent GSH peroxidase (SeGSHpx) and GSSG reductase (GSSGred) in confluent monolayers of human umbilical vein endothelial cells derived from 4 individual donors. The mean levels of GSH in confluent monolayers of individual human umbilical vein endothelial cells batches fell from an average of 35 nmol/mg protein to 16 nmol/mg protein from primary culture to the third passage, with little interindividual variation noted. Simultaneously, the mean activities of SeGSHpx and GSSGred remained unaltered during serial culture, again with little interindividual variation noted. However, serial passage of the cells from different individuals did not affect the sensitivity of the cells to sublethal injury induced by H2O2 (10 or 100 μM), as judged by the stimulated release of (3H)‐deoxyglucose. When these GSH‐dependent parameters were assayed during the coarse of the growth of an individual passage of cells, GSH levels declined following trypsinisation, but the activities of SeGSHpx and GSSGred remained essentially unaltered, when the data were standardised to cell number. On the other hand, standardisation of these data to cell protein revealed decreases in all three parameters following trypsinisation, indicating the introduction of artefacts into the data and the unsuitability of this standardisation procedure. For the first four hours following plating, all of the GSH‐dependent parameters remained essentially unaltered, but began increasing thereafter. Thus, GSH levels climbed to a peak prior to the onset of cell division and the activity of GSSGred rose to a peak by 24 hr, whilst the activity of SeGSHpx rose steadily during the first 72 hr of culture. When these low density cell cultures were tested for their sublethal response to H2O2 (3, 10 and 100 μM), a dose‐dependent increase in the release of (3H)‐deoxyglucose was noted, which remained constant during the first 72 hr of culture. Due to the relative lack of interindividual variations in the GSH parameters tested and in the sensitivity to H2O2, these data suggest that confluent cultures of pooled cells of any passage up to the third may be used for model studies of the sublethal effects of H2O2 in these human cells. The data also suggest that the sensitivity of confluent human umbilical vein endothelial cells derived from different individuals to the sublethal effects of H2O2 is not predictable from their individual GSH‐dependent potential to detoxicate the peroxide. Additionally, fluctuations in GSH‐dependent potential to detoxicate H2O2 may be related to the onset of growth in sub‐confluent cultures of human umbilical vein endothelial cells, but appear, once again, not to be related to the sensitivity of the cells to sublethal effects of H2O2.
Drug and Ethanol Effects on the Clinical Test for Drunkenness: Single Doses of Ethanol, Hypnotic Drugs and Antidepressant Drugs
Authors: Kuitunen T.
Published: March 2009

Abstract: The clinical test for drunkenness has been used in Finland to detect alcohol‐induced impairment of driving fitness. Since the data about the effects of psychotropic drugs on the clinical test for drunkenness are limited, this test was administered in two randomized double‐blind cross‐over trials with 12 subjects in each. The clinical tests were done at 2 hr and 5 hr after drug intake. For comparison, the representative laboratory tests used were digit symbol substitution, simulated driving (tracking + reaction time) and “global psychomotor performance”. In Trial I, 15 mg of diazepam, 50 mg of amitriptyline and 15 mg of mirtazepine, each drug administered alone, had minor effects on the clinical tests. Compared to the placebo, mirtazepine, and diazepam, diazepam + mirtazepine impaired performance on the motor subtests at 2 hr. The tracking error percentage was increased by amitriptyline, diazepam + amitriptyline, and diazepam + mirtazepine up to 4.5 hr. In Trial II with 7.5 mg of zopiclone, 0.25 mg of triazolam and 0.8 g/kg of ethanol, ethanol alone and hypnotic‐ethanol combinations impaired performance on the motor and vestibular subtests, whereas single drug intake had minor effects. Tracking was more sensitive to drugs than to ethanol. In conclusion, the clinical test for drunkenness detected impaired performance following single doses of ethanol or drug‐ethanol combinations better than it detected impaired performance following moderate doses of drugs or drug‐drug combinations, respectively.
Nicotine in Hair of Smokers and Non‐Smokers: Sampling Procedure and Gas Chromatographic/Mass Spectrometric Analysis
Authors: Zahlsen K. , Nilsen O. G.
Published: March 2009

Abstract: A gas chromatographic/mass spectrometric method for analysis of nicotine in scalp hair and measurements of nicotine in hair from 20 smokers and non‐smokers with a one year interval are presented. The gas chromatographic/mass spectrometric method, based on selected ion monitoring of the ion m/z 162, with ions m/z 133 and 84 as qualifier ions, allows a highly selective and sensitive detection of nicotine in hair samples avoiding interference from other chemicals present in hair. Nicotine is extracted after alkaline dissolution i 5M NaOH. The sampling procedure takes into account that significant amounts of nicotine in hair is probably adsorbed and deposited from atmospheric air. In consequence, the hair samples must be taken from a site with sufficient contact with surrounding air and the measured concentration of nicotine must be related to the length of the hair segment and its distance from the scalp. Our study demonstrated very clear and statistically significant differences in the concentrations of nicotine in hair from smokers and non‐smokers, a high reproducibility of hair nicotine measurements over time, and that the presented method is sensitive enough to detect individual changes not only in smoking habits, but also in environmental nicotine exposure.
Sensory Irritation Effects of n‐Propanol and Ethylbenzene after Pretreatment with Capsaicin or Indomethacin
Authors: Hansen Lea Frimann , Nielsen Gunnar Damgård
Published: March 2009

Abstract:Irritation of upper respiratory tract (sensory irritation) due to two model solvents, ethylbenzene and propanol, were investigated from their reflex‐induced decrease in respiratory rate in mice. Intranasal application of capsaicin decreased the sensory irritation response of both solvents, indicating that at least part of the sensory irritation effect must occur as a result of activation of capsaicin sensitive afferent nerves. The vehicle used for the application of capsaicin in itself decreased the respiratory rate strongly, either caused by effects on the upper respiratory tract or on the lungs. This demonstrates the need for a formulation of a pharmacologically inactive vehicle for nasal application of lipophilic substances. Pretreatment with indomethacin had no influence on sensory irritation of any of the solvents. This suggests that sensory irritation is caused by a direct interaction between receptors on the trigeminal nerves and the vapours rather than being an indirect effect of tissue damage giving rise to metabolites from the cyclooxygenase pathway.
Effect of Chronic Treatment with ICI D7114, a Selective β3‐Adrenoceptor Agonist, on Macronutrient Selection and Brown Adipose Tissue Thermogenesis in Sprague‐Dawley Rats
Authors: Santti Eriika , Rouvari Taina , Rouru Juha , Huupponen Risto , Koulu Markku
Published: March 2009

Abstract: ICI D7114 is a selective β3‐agonist which stimulates brown adipose tissue thermogenesis. In the present study the effects of 18 days treatment with ICI D7114 (2 mg/kg/day orally) on macronutrient selection and brown adipose tissue thermogenesis were investigated in Sprague‐Dawley rats. The rats were maintained on a free‐feeding self‐selection paradigm with three pure macronutrient diets of carbohydrate, fat and protein. Treatment with ICI D7114 did not change the macronutrient selection or total calories consumed by the rats. To monitore the thermogenic activation of brown adipose tissue the binding of [3H]GDP to brown adipose tissue mitochondria was measured. The treatment with ICI D7114 increased the binding of GDP both when expressed as total binding per lobe (P<0.001) and per mg of protein (P<0.01). It is concluded that ICI D7114, used in doses affecting brown adipose tissue thermogenesis, does not change the macronutrient selection or total energy intake in Sprague‐Dawley rats.
The Effect of Captopril on the Oxidation of Plasma Lipoproteins
Authors: Clearfield Michael B. , Lee Nam , Armstrong Larry , DeFazio Peggy , Kudchodkar B. J. , Lacko Andras G.
Published: March 2009

Abstract:The antihypertensive drug captopril was found to inhibit the oxidation of low density lipoproteins by copper in a dose dependent mannerin vitro. Up to 65% inhibition of oxidation was observed at the concentration of 100 μg/ml of captopril. During subsequent studies with patients, captopril protected low density lipoproteins against oxidation slightly better than enalapril, although this difference was not statistically significant. Captopril had no effect on the levels of Lp(a) as compared to the levels established during enalapril treatment.
Effect of Levomepromazine and Metabolites on Debrisoquine Hydroxylation in the Rat
Authors: Hals Petter‐Amt , Dahl Svein G.
Published: March 2009

Abstract:The influence of the major metabolites of the phenothiazine derivative, levomepromazine (methotrimeprazine), on hydroxylation of debrisoquine was examined in male Sprague‐Dawley rats. The metabolic ratio of debrisoquine/4‐hydroxy debrisoquine was first determined in rats after oral administration of 10 mg/kg of debrisoquine. Then the same dose of debrisoquine was co‐administered with various doses of levomepromazine or one of its metabolites. Levomepromazine and its sulphoxidated, N‐demethylated and O‐demethylated metabolites caused highly significant and dose‐dependent increases in the debrisoquine metabolic ratio. 3‐Hydroxy levomepromazine had no significant effect on the metabolism of debrisoquine. This indicates that the non‐hydroxylated metabolites of levomepromazine have relatively high affinities for the cytochrome P450 enzyme which converts debrisoquine to 4‐hydroxy debrisoquine in the rat. Such metabolites may therefore be responsible for a considerable part of the inhibitory effect of debrisoquine hydroxylation previously reported in patients treated with phenothiazine neuroleptics.
Newer Neuromuscular Blocking Agents
Authors: Bevan David R.
Published: March 2009

Four neuromuscular blocking drugs, doxacurium, mivacurium, pipecuronium, and rocuronium have been or are about to be introduced into clinical practice. The purpose of this MiniReview is to describe their pharmacology, to consider their place in clinical anaesthetic practice, and to examine whether the needs of the clinican have been met. Two of the agents (doxacurium, mivacurium) are benzylisoquinolines resembling atracurium and two (pipecuronium, rocuronium) are aminosteroids related to pancuronium and vecuronium. Two (doxacurium, pipecuronium) are long‐acting compounds, similar in duration of action to pancuronium, although the need for such a profile is questionable. Rocuronium has an intermediate duration of action and produces its maximum effect within two minutes which is much more rapid than any other non‐depolarizing relaxant and this is probably a result of its poor potency. However, the onset of paralysis is not as quick as after succinylcholine. Mivacurium is unique because it is metabolized by plasma cholineslerase which produces a rapid recovery although slower than succinylcholine. All of the new drugs are devoid of serious cardiovascular or other side effects. The anaesthetist is now presented with an armamentarium of safe, non‐depolarizing muscle relaxants with varying durations of action. However, the rapid onset and recovery associated with succinylcholine are unique and important in the urgent control of a patient's airway and respiration. The indications for succinylcholine will not disappear and the search for a non‐polarizing replacement will continue.
Effects of Terbutaline on α‐Adrenergic Responses and Ca2+Influx in Isolated Rabbit Aorta
Authors: Hsu Chia‐Hsuh , Robinson Casey P.
Published: March 2009

Effects of terbutaline appliedin vivoorin vitroon α‐adrenergic receptors in the rabbit aorta in normal and Ca2+–free solution, and on basal, high potassium‐, and phenylephrine‐stimulated Ca2+uptake into aorta were investigated. Three day terbutaline administration (25 mg/kg, subcutaneously three times daily) to rabbits increased the pKBfor phentolamine in aorta rings (control 7.3 + 0.2, n = 9; terbutaline 7.8 +0.2, n = 15). It also depressed phenylephrine‐stimulated contractions of aorta rings in Ca2+–free but not those in normal Krebs solution. It did not significantly depress the basal, or phenylephrine‐evoked Ca2+influx into aorta rings, but decreased high potassium‐induced Ca2+–influx (control 0.58 + 0.05 umoles/g aorta; n = 3, terbutaline 0.41 +0.06 umoles/g aorta, n = 3).In vitroapplication of 50 μM terbutaline did not significantly alter phenylephrine‐stimulated contractions of aorta rings in Ca2+–free Krebs solution or significantly depress basal or phenylephrine‐induced Ca2+influx into aortas, but did decrease high potassium‐stimulated Ca2+–influx. Thus, 3‐day terbutaline administration increased the affinity of α‐adrenergic receptors for phentolamine and had a tendency to increase contractions of aorta rings to phenylephrine. It also decreased high potassium‐stimulated Ca2+influx, and depressed phenylephrine‐induced contractions in Ca2+–free Krebs solution, whilein vitroterbutaline application also decreased potassium‐induced Ca2+influx.
Cadmium Mobilization by Monoaralkyl‐ and Monoalkyl Esters ofmeso‐2,3‐Dimercaptosuccinic Acid and by a Dithiocarbamate
Authors: Jones Mark M. , Singh Pramod K. , Basinger Mark A. , Gale Glen R. , Smith Alayne B.
Published: March 2009

Syntheses and relative cadmium mobilizing properties are described for three new monoaralkyl esters (HOOCCH(SH)CH(SH)COOR, where R = phenylethyl ((CH2)2C6H5), MPhEDMS; R = 3‐phenylpropyl ((CH2)3C6H5), MPhPDMS; and R = 2‐phenoxyethyl ((CH2)2OC6H5), MPhOEDMS) ofmeso‐2,3‐dimercaptusuccinic acid. These were prepared by the reaction of the corresponding alcohol withmeso‐2,3‐dimercaptosuccinic acid (DMSA) in aqueous HCl. When administered intraperitoneally to cadmium‐loaded mice at 0.50 mmol/kg/day for four consecutive days, all induced significant reductions in the whole body cadmium levels. MPhEDMS, 60%; MPhPDMS, 66%; and MPhOEDMS, 58% in comparison with control levels. At the same dosage monoisoamylmeso‐2,3‐dimercaptosuccinate (Mi‐ADMS) and a dithiocarbamate, sodiumN‐benzyl‐4‐O‐(β‐D‐galactopyranosyl)‐d‐glucamine‐N‐carbodithioate (BLDTC) induced reductions of 65% and 57%, respectively. Hepatic and renal cadmium were also depleted significantly, while brain cadmium levels were unchanged. These compounds induced a significant reduction in the cadmium levels of the spleen, and one, MPhOEDMS, produced a 10% decrease in pancreatic cadmium. The manner in which the later injections removed smaller fractions of the total body cadmium is consistent with a bodily distribution of these compounds by which they are concentrated primarily in the kidneys and the liver, with much smaller amounts reaching other organs. It is proposed that these compounds enter renal and hepatic cells through an anion transport system.
The Effect of Three Products of Cigarette Smoke (Cyanide, Thiocyanate and Nicotine) on the Concentration‐Response Curves of 5‐Hydroxytryptamine, Norepinephrine and Epinephrine in the Isolated Human Umbilical Veins and Arteries
Authors: Tunçel Neşe , Aydin Yasemin , Tikiz Hakan
Published: March 2009

The effect of cyanide (10−7M), thiocyanate (10−4M) and nicotine (10−7M) on the concentration‐response curves of 5‐hydroxytryptamine, norepinephrine and epinephrine were investigated in human isolated umbilical arteries and veins. Cyanide significantly affected the responses of arterial strips to 5‐hydroxytryptamine, norepinephrine and epinephrine: It caused significant leftward shifts of the 5‐hydroxytryptamine concentration‐response curves and significantly potentiated the contractile effects of norepinephrine and epinephrine in the case of norepinephrine, and epinephrine concentration reached 10−6and 10−7M respectively in the bath medium. Cyanide did not show any significant effect on the concentration‐response curves of 5‐hydroxytryptamine, norepinephrine and epinephrine in veins. Nicotine interacted with the response of adrenergic agonists both in arteries and veins; in arteries it potentiates the contractile response of epinephrine; in veins, it inhibited the dilatory responses of norepinephrine and potentiated the contractile effect of high concentration of epinephrine (10−6M). Thiocyanate did not cause any difference on any cumulative concentration‐response curves either on the vessels. However, none of these individual effects of cyanide and nicotine were observed when the cyanide, thiocyanate and nicotine were added in combination in the isolated organ bath medium.
Effect of Ascorbate on Adriamycin‐Fe3+–Induced Lipid Peroxidation and DNA Damage
Authors: Miura Toshiaki , Muraoka Sanae , Ogiso Taketo
Published: March 2009

Adriamycin‐Fe3+‐induced lipid peroxidation was enhanced by ascorbate at low concentrations. High concentrations of ascorbate also enhanced the peroxidation reaction, but only at an early stage. The initial rate of peroxidation depended upon the ratio of adriamycin‐Fe2+/adriamycin‐Fe3+and the maximum rate was observed at the ratio of 1:1. These results suggest that the adriamycin‐Fe3+‐induced lipid peroxidation may be initiated by an adriamycin‐Fe2+–oxygen‐adriamycin‐Fe3+complex. Ascorbate also promoted bathophenanthroline‐Fe2+formation from adriamycin‐Fe3+in a dose‐dependent manner. It seems likely that ascorbate influences the peroxidation reaction via the reduction of adriamycin‐Fe3+. During the interaction of adriamycin‐Fe3+with ascorbate, deoxyribose was not degraded, suggesting that hydroxyl radical formation did not occur. In contrast, plasmid PM2 DNA was readily damaged during the interaction of adriamycin‐Fe3+with ascorbate. Catalase, mannitol and dimethylsulfoxide prevented DNA damage. No DNA damage occured when the reaction was run under nitrogen gas, indicating that oxygen is involved.
One‐year Treatment of Non‐Diabetic and Streptozotocin‐Diabetic Rats with Vanadyl Sulphate Did not Alter Blood Pressure or Haematological Indices
Authors: Dai S. , McNeill J. H.
Published: March 2009

Circulatory and haematological effects of chronic administration of vanadyl sulphate in drinking water for one year in non‐diabetic and streptozotocin‐diabetic rats were investigated. At various time points during the treatment period and at 13 weeks following its withdrawal, systolic blood pressure and pulse rate were measured using a tail‐cuff method and some selected haematological indices, including haematocrit, haemoglobin, erythrocyte count, reticulocyte percentage, leukocyte count, platelet count, and leukocyte composition of the peripheral blood were determined using standard methods. It was found that prolonged treatment of either nondiabetic or streptozotocin‐diabetic rats with vanadyl sulphate did not cause significant changes in the parameters observed but significantly alleviated the occurrence of bradycardia and the decreased leukocyte count in the peripheral blood in streptozotocin‐diabetic animals. No significant changes in systolic blood pressure, pulse rate, or haematological indices were observed following the withdrawal of vanadyl sulphate, except that the previously vanadyl‐treated diabetic rats were found to have higher leukocyte count, platelet count and neutrophil percentage, and lower lymphocyte percentage in their leukocyte compositon. It is concluded that vanadyl sulphate does not have a hypertensive effect nor is it significantly toxic to the haemopoietic system in rats.
The Cardiovascular Effects of Ricin in Rabbits
Authors: Christiansen Victoria J. , Hsu Chia‐Hsuh , Dormer Kenneth J. , Robinson Casey P.
Published: March 2009

Ricin is a toxic lectin from the castor bean. The time course of its toxic effects on the cardiovascular system of rabbits was investigated after determining its LD50 and minimum lethal dose in rabbits by the Up and Down method, as a basis for dosing. Systolic and diastolic arterial pressures, electrocardiogram and heart rate were recorded for 48 hr following administration of either a toxic sublethal (0.22 μg/kg) or minimum lethal dose (0.44 μg/kg) of ricin. After a delayed onset of about 20 hr, the minimum lethal dose (0.44 μg/kg) of ricin caused a significant decrease in both systolic and diastolic pressures (P<0.05). The systolic and diastolic pressures decreased 0.47 and 0.39 mmHg/hr more so than control groups, respectively. A toxic sublethal dose (0.22 μg/kg) of ricin did not significantly alter either systolic or diastolic pressure. Neither dose of ricin caused cardiac arrhythmias or significantly increased heart rate. We conclude that the lethal hypotensive sequelae of ricin toxicity in the rabbit were peripheral in origin and not cardiogenic at these two doses.
Should Probenecid be Used to Reduce the Dicloxacillin Dosage in Orthopaedic Infections? A Study of the Dicloxacillin‐Saving Effect of Probenecid
Authors: Krogsgaard Michael R. , Hanson Bjørn Asser , Slotsbjerg Torsten , Jensen Pia
Published: March 2009

Reduction in the dosage of dicloxacillin from 500 mg to 250 mg 3 times a day would mean lowering of costs and less side‐effects in orthopaedic infections. In this cross‐over study, the serum concentrations of dicloxacillin were measured in 9 patients after administration of dicloxacillin 500 mg 3 times a day (dicloxacillin 500 mg) and after coadministration of 250 mg dicloxacillin and 250 mg probenecid 3 times per day (dicloxacillin 250 mg + probenecid 250 mg). Concentrations were measured every hour after the tablet intake. The mean maximum serum concentrations of dicloxacillin were 17.1 μg/ml (dicloxacillin 500 mg) and 12.2 μg/ml (dicloxacillin 250 mg + probenecid 250 mg). respectively (P<0.05). Serum concentrations above 3 μg/ml were obtained during 285 min. in both regimes, but the individual variations were biggest during in the dicloxacillin 250 mg + probenecid 250 mg treatment. Serum concentrations above 5 μg/ml were in mean measured during 228 min. (dicloxacillin 500 mg) and 190 min. (dicloxacillin 250 mg + probenecid 250 mg), respectively (P<0.05). The clinical significance of these findings is being discussed. In theory, treatment with dicloxacillin 250 mg + probenecid 250 mg may be as sufficient as dicloxacillin 500 mg.
Functional and Antiischaemic Effects of the Phosphodiesterase Inhibitor Levosimendan in Isolated Rabbit Hearts
Authors: Rump A. F. E. , Acar D. , Rösen R. , Klaus W.
Published: March 2009

Several phosphodiesterase inhibitors have been reported to possess antiischaemic properties by improving myocardial oxygen demand/supply balance. Levosimendan is a new phosphodiesterase inhibitor with calcium‐sensitizing properties. We investigated the functional and anliischaemic properties of levosimendan in isolated electrically‐driven rabbit hearts (Langendorff, constant perfusion pressure: 70 cm H2O, Tyrode solution, Ca++ 1.8 mmol/1, 37°, 200 beats/min.). Acute regional myocardial ischaemia was induced by ligature of a circumflex artery branch and quantified from epicardial NADH‐fluorescence photography. Results: The left ventricular pressure was similarly enhanced by levosimendan 10−7 M or 5 × 10−6 M (+15%) (P<0.05). The global coronary flow was increased more markedly by levosimendan 5 × 10−6 M (+ 35‐50%) compared to 10−7 M (+ 25%) (P<0.05). The relative coronary flow (= global coronary How/pressure‐rate‐product) was significantly enhanced only by levosimendan 5 × 10−6 M (+ 20‐35%) (P<0.05), but not by levosimendan 10−7 M (+10‐15%) (P>0.05). Epicardial NADH‐fluorescence area and intensity were significantly diminished by levosimendan (‐20%) (P<0.05), and there was no significant difference between myocardial ischaemia reduction by levosimendan 10−7 M and 5 × 10−6 M (P>0.05). Conclusion: Levosimendan is an inotrope with coronary dilator activity, showing antiischaemic effects in isolated rabbit hearts. These may be caused by (1) phosphodiesterase‐inhibition and improvement of myocardial perfusion and/or (2) by oxygen‐sparing effects, related to calcium sensitization of myofilaments, particularly at lower concentrations associated with a lower coronary dilator activity.
Acetone Potentiation and Influence on the Reversibility of 2,5‐Hexanedione‐Induced Neurotoxicity Studied with Behavioural and Morphometric Methods in Rats
Authors: Ladefoged Ole , Roswall Karen , Larsen Jens‐Jørgen
Published: March 2009

The neurobehavioural and morphologic changes and the reversibility in 2,5‐hexanedione‐induced polyneuropathy in rats were studied. The potentiation and influence of acetone on the reversibility of the induced neurotoxicity was also evaluated. Male rats were treated for 6 weeks with 0.5% w/v 2,5‐hexanedione alone or in combination with 0.50% w/v acetone in the drinking water. During the treatment period, neurobehavioural tests (ambulation and rearing in open field, balance on the accelerating rotarod and fore‐and hindlimb muscle strength measurements) were performed weekly. After 6 weeks half of the rats was sacrificed and histopathological lesions in the sciatic nerve and tibial nerve were evaluated by morphometry. Neurotoxicity was induced by 2,5‐hexanedione, and acetone caused a potentiation of this effect in open field ambulation and rearing and in the rotarod test. In the pathological evaluation, giant axonal swelling was observed after 2,5‐hexanedione and 2,5‐hexanedione plus acetone. In nerve fibre cross sections, a significant change of the distribution of fibre area size was observed in animals treated with 2,5‐hexanedione. Aggravation of the lesions was seen in rats treated with both 2,5‐hexanedione and acetone. The other half of the animals was used to study the reversibility of the neurotoxic effects within a dose‐free period of 10 weeks. Reversibility of the effect on ambulation was complete within the recovery period, but the effects on rearing and balance in the rotarod test were only reversible within the 10 weeks in the 2,5‐hexanedione‐treated rats and not in the combined 2,5‐hexanedione and acetone‐treated rats. The reduction in muscle strength was not reversible. Reversibility of the giant axonal swelling was seen within the recovery period. However, the normalization of the fibre size distribution of the large fibre was only seen in the tibial nerve and not in the sciatic nerve. It is concluded that acetone potentiates the 2,5‐hexanedione‐induced neurotoxicity as measured as enhancement of the behavioural and morphological changes. The combined acetone and 2,5‐hexanedione effects are similar to the effects of 2,5‐hexanedione alone. The most probable mechanism of action of the acetone potentiation is an effect on the toxicokinetics of 2,5‐hexanedione. The combined neurotoxic effects of acetone and 2,5‐hexanedione are not reversible within a recovery period of 10 weeks.
Pharmacological Characterization of a Biosynthetic Trisulfide‐Containing Hydrophobic Derivative of Human Growth Hormone: Comparison with Standard 22 K Growth Hormone
Authors: Thomsen Mads Krogsgaard , Hansen Birgit Sehested , Nilsson Povl , Nowak Jette , Johansen Peter Bygballe , Thomsen Preben Damsgaard , Christiansen Jesper
Published: March 2009

Growth hormone is the classical anabolic hormone which promotes organ growth after binding to somatogenic target cell receptors, present in various target tissues. The present study elucidated the pharmacological characteristics in vitro and in vivo of human growth hormone and a recently identified by‐product of a recombinant human growth hormone preparation; i.e. a trisulfide‐containing (cys 182‐cys 189) hydrophobic, folding derivative of growth hormone, hydrophobic derivative‐growth hormone. Standard growth hormone and hydrophobic derivative‐growth homone possessed similar characteristics in vitro, both as regards binding to the somatogenic receptor on the human IM‐9 cell line, and the prolactin receptor‐mediated proliferation of rat Nb2 cells. This indicates that no change occurs in the binding characteristics in spite of a change in conformation of the molecule. Using an ELISA assay that detected standard and hydrophobic derivative‐growth hormone equally well, the plasma pharmacokinetical profiles of the preparations following a single intravenous or subcutaneous dose were indistinguishable. Thus, following initial disposition of hydrophobic derivativegrowth hormone and standard growth hormone into a volume, Vl, of one to two times the plasma volume, almost 90% of either compound disappeared from plasma during the α‐phase of the plasma decay curve. Similar half‐lives of 4‐5 min. were found for hydrophobic derivative‐growth homone and standard growth hormone during this phase, indicating rapid removal of drug from the circulation. Also, the AUC and Cmax values for standard and hydrophobic derivativegrowth hormone did not differ following intravenous or subcutaneous administration. Examination of whole body autoradiograms following dosing with 125I‐labeled standard growth homone revealed intensive staining of the liver and renal cortex, suggesting elimination via these organs. Finally, and concording with the in vitro and in vivo bioequivalence of hydrophobic derivative‐growth hormone and standard growth hormone, anabolic action of the hydrophobic derivativegrowth hormone in the tibia test was shown to be fully retained. In conclusion, pharmacological profiling has been performed for standard growth hormone and a cys 182‐cys 189 trisulfide‐containing hydrophobic growth hormone derivative, and no differences were detected between the two in vitro or in vivo.
Epidemiological and Financial Aspects of the Use of Non‐Steroidal Anti‐Inflammatory Analgesics
Authors: Paakkari Ilari
Published: March 2009

Abstract The availability of many new nonsteroidal anti‐inflammatory drugs (NSAIDs) has increased the total consumption during the past 20 years. The cost of different NSAID brands varies considerably probably reflecting increased research and development costs rather than a true therapeutic benefit for the patient. The current therapeutic problem in the treatment of musculoskeletal conditons with NSAIDs is to make a balanced analysis between benefits, risks, and costs. Assessment of risks and benefits should focus on the large subgroup (about 40%) of elderly NSAID users over 60 years who clearly stand at increased risk of NSAID‐induced gastrointestinal complications. In the treatment of osteoarthritis more trials are needed to compare NSAIDs with plain analgesics (e.g. paracetamol).
Tolfenamic Acid: Clinical Experience in Rheumatic Diseases
Authors: Isomäki Heikki
Published: March 2009

Abstract Tolfenamic acid (TA) is an interesting drug for the treatment of rheumatic diseases because of its capacity to inhibit the synthesis of leukotrienes. It may have fewer upper gastrointestinal side effects than other NSAIDs which inhibit only the synthesis of prostaglandins. Several controlled and non‐controlled studies on the clinical efficacy and side effects of TA have been carried out since the early seventies. These studies include about 900 patients suffering from different rheumatic diseases. The clinical efficacy of TA has proved to be at least as good as that of control drugs in all double‐blind trials. We have compared the analgesic effect of ten NSAIDs in patients with rheumatoid arthritis, using a single‐blind method by asking the patients which one of two drugs was the better. The study gave a rank order to the drugs favoured by the patients and the results showed that TA was among the four best drugs together with naproxen, indomethacin, and diclofenac. The side effect profile of TA is different from that of other NSAIDs. The number of upper gastrointestinal side effects during TA treatment was less than half the number during treatment with control NSAIDs in eight double‐blind studies. On the other hand, dysuria was found only during TA treatment. In 1989 the official side effect registers of Denmark and Finland included a total of 462 side effect reports. The frequency of side effects per treatment day was about the same as for other NSAIDs according to these reports. Allergic skin reactions represented 40% of all reported side effects, dysuria 19%, diarrhoea 10%. and upper gastrointestinal symptoms (dyspepsia, nausea, vomiting, gastric pain, and ulcer) only 6%. TA is an effective NSAID with a short half‐life, and probably has fewer upper gastrointestinal side effects than NSAIDs with no effect on the leukotriene synthesis.
Tolfenamic Acid and Migraine‐Aspects on Prostaglandins and Leukotrienes
Authors: Vapaatalo Heikki
Published: March 2009

Abstract Migraine is a paroxysmal disorder characterized by recurrent attacks of headache, with or without associated visual and gastrointestinal disturbances. Migraine can be classified in two main groups, common and classic. Theories trying to explain the pathogenesis of a migraine attack may emphasize either the central or peripheral aspects of the disease. The vascular theory may stress the importance of either central or peripheral blood flow or both. Cerebral vasoconstriction in the early phases of the attack is followed by vasodilatation and pain. Biochemical mediators of vascular responses are not exactly known, but platelets and 5‐hydroxytryptamine and thromboxane released from them as well as noradrenaline are potent vasoconstrictors. while kinins and prostaglandins can explain the vasodilatory phase of migraine attacks. This review presents evidence for the role of arachidonic acid metabolites, prostaglandins and leukotrienes in migraine. The evidence comes from the measurements of eicosanoids in biological fluids during and after the attack, infusion studies where vasodilatory prostaglandins mimic the migraneous symptoms, and the good effect of non‐steroidal anti‐inflammatory drugs in the treatment and prophylaxis of migraine attacks. Additional data are based on experimental biochemical studies in which catecholamines and indolamines have been shown to increase the synthesis of vasodilatory prostaglandins. However, the final evidence still awaits its confirmation.
Tolfenamic Acid and Mefenamic Acid in the Treatment of Primary Dysmenorrhoea
Authors: Delgado Jorge , Simonin Guadalupe , Servier Claudio , García Raúl , Yoma Jorge
Published: March 2009

Abstract The clinical efficacy of tolfenamic acid and mefenamic acid in the treatment of primary dysmenorrhoea was studied in a prospective, controlled, double‐blind, cross‐over study comprising 73 patients aged 13‐39 with an average body weight of 56 kilos. The patients were randomized to receive either tolfenamic acid (200 mg t.i.d.) or mefenamic acid (500 mg t.i.d.) for 3 days, during 3 consecutive menstrual cycles each, in a sequential design A‐B or B‐A. At the beginning and at the end of each treatment period, 13 dysmenorrhoeic symptoms were evaluated on a visual analogue scale (lower back pain, interference with daily activities, nausea, vomiting, diarrhoea, headache, dizziness, fatigue, sweating, chills, hot flashes, depressant states, and mood swings). The data were analysed by using two statistical models. The first one, for the 73 patients, by making paired comparisons regardless of treatment sequence. With respect to the initial values, the results showed that both drugs were statistically significant (P<0.05) in reducing the intensity of the evaluated symptoms. When comparing both treatments, tolfenamic acid showed a significant difference as to interference with daily activities (P<0.025) and hot flashes (P< 0.005). In the result analysis with the second model, the groups were divided according to the first assigned treatment and paired comparisons were made. It was observed that the group receiving tolfenamic acid in the last sequence reached a higher level of response and statistical significance was demonstrated in 8 of 13 evaluated symptoms. There were no differences with respect to duration of menstruation and volume of menstrual bleeding. Both drugs were well tolerated. Side effects were observed in 4 patients (5.5%) during tolfenamic acid treatment and 5 patients (6.8%) during mefenamic acid. These symptoms were of mild intensity and did not require cessation of treatment. They consisted of nausea and abdominal pain. Conclusion: On the basis of our results it was shown that tolfenamic acid was more effective than mefenamic acid in the treatment of primary dysmenorrhoea.
The Effects of Drugs Acting at GABA‐Benzodiazepine‐Barbiturate Receptor Complex on the Behaviour of Sleep‐Deprived Mice
Authors: Pokk P. , Zharkovsky A.
Published: March 2009

Abstract: The effects of the benzodiazepine receptor agonist diazepam, the benzodiazepine receptor antagonist flumazenil and the benzodiazepine receptor inverse agonist ethyl‐8‐azido‐5, 6‐dihydro‐5‐methyl‐6‐oxo‐4H‐imidazo‐[1, 5‐a] [1‐4] benzo‐diazepine‐3‐carboxylate (RO 15‐4513) on the locomotor activity and the behaviour of animals in the plus‐maze test were studied in sleep‐deprived mice. The effects of convulsants acting at GABA‐benzodiazepine‐barbiturate receptor complex‐bicuculline, picrotoxin and pentylenetetrazole, were also studied. Sleep deprivation of mice for 24 hr using the platform technique caused behavioural excitation that was reflected by an increase in the locomotor activity. Administration of diazepam (0.5 and 2.0 mg/kg), flumazenil (5.0 and 10.0 mg/kg) and RO 15‐4513 (1.0, 2.0 and 3.0 mg/kg) either did not affect (in low doses) or inhibited (in high doses) locomotions of control animals. The inhibition of locomotor activity by these drugs was greater in sleep‐deprived animals. In the plus‐maze test, diazepam in a dose of 2.5 mg/kg had an anxiolytic effect in control mice that was reflected by an increase in the percentage of entries onto and the percentage of time spent on the open arms of the plus‐maze. In contrast, in sleep‐deprived animals, diazepam did not induce anxiolytic action at any dose tested. In the highest dose (2.5 mg/kg) diazepam produced a sedative effect that was reflected by a decrease in the total number of entries made onto the open and into the closed arms of the plus‐maze. The convulsive actions of bicuculline (2.0–4.0 mg/kg) and picrotoxin (2.5–4.0 mg/kg) were considerably more pronounced in sleep‐deprived mice as compared to control animals. The effect of pentylenetetrazole (60–100 mg/kg) was not changed in sleep‐deprived mice. These data suggest that sleep deprivation induced a sensitization of mice to the motor depressant effect of benzodiazepine receptor agonists, antagonists and inverse agonists and to the convulsive action of bicuculline and picrotoxin. At the same time sleep deprivation induces a hyposensitivity of mice to the anxiolytic effect of diazepam. It is proposed that the hyposensitivity to the anxiolytic effect of diazepam as well as the hypersensitivity to the convulsions induced by bicuculline and picrotoxin in sleep‐deprived mice might be due to the alterations in the function of GABA‐benzodiazepine‐barbiturate complex induced by sleep deprivation.