bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetic Differences of Desmethyldiazepam in Three Outbred Wistar Strains Related to Differences in Liver Enzyme Activities
Authors: van der Laan J. W. , de Groot G. , Wortelboer H. , Noordhoek J.
Published: March 2009

Various strains of rats differ in their sensitivities towards benzodiazepines suggesting that variations in biological features are responsible for these differences. All reports concern inbred strains. We have studied male rats of three outbred Wistar strains with regard to the pharmacokinetics of desmethyldiazepam given as a single intravenous dose. The elimination half‐life of desmethyldiazepam was longer in the Riv:TOX(M) (from the National Institute of Public Health and Environmental Protection) and in the Cpb:WU strain than in the Crl:(WI)BR strain. This strain difference in elimination of desmethyldiazepam may be related to differences in liver enzyme activities.
Electroencephalographic Effects of Flucloxacillin in Rats
Authors: Contreras S. , Kramer M. V. , Pesce M. E.
Published: March 2009

Abstract: The neurotoxicity of flucloxacillin, an isoxazolyl derivative of β‐lactamic antibiotics, was studied in rats by electroencephalographic recordings. The results show that intravenous flucloxacillin, (200 mg/kg) produced cortical activity modifications. The changes in electroencephalogram consist of irritative activity patterns and bursts of high voltage waves with spikes and polyspikes. The effects of other β‐lactamic drugs (cloxacillin, ampicillinsulbactam and penicillin G) on electroencephalography activity were also investigated after intravenous administration of equivalent doses. These drugs did not change the normal bioelectric cerebral activity of the rats.
Up‐regulation of Polysialic Acid in Peripheral Myelinated Axons of Rat Chronically Exposed to 2,5‐Hexanedione
Authors: Carratù M. R. , Labate M. , Santis S. De , Lacomba C. , Cuomo V.
Published: March 2009

Abstract: Myelinated nerve fibres isolated from Wistar rats chronically exposed to 2,5‐hexanedione (0.8 ml/kg/day, intraperitoneally) over a period of 20 days, were stained with lectin‐horseradish peroxidase conjugates. The lectins with high affinity for terminal D‐galactopyranosyl residues, Bandeiraea simplicifolia‐B4 (BSA I‐B4) and peanut agglutinin (PNA), showed glycoconjugates in the control nodes of Ranvier. In the treated animals, application of PNA‐HRP caused weak reactivity to the node of Ranvier; digestion with sialidase prior to the application of PNA‐HRP conjugate enhanced reactivity, thus revealing the presence of a sialoglycoprotein. The results indicate that glycoconjugates of the Ranvier node undergo a rearrangement during exposure to 2,5‐hexanedione. In particular, neutral glycoproteins with terminal galactose are replaced by sialoglycoproteins. These findings are consistent with the proposed role of polysialic acid as a regulator of axonal behaviour during regeneration.
Radioprotective Effects of the Association Thymopentin‐Interleukin‐1α in the C57BL/6 Mouse
Authors: Barbera N. , Palmucci T. , Chiarenza A. , Bartoloni G. , Cordaro S. , Greco S. , Scapagnini U. , Bernardini R.
Published: March 2009

Abstract: We investigated whether thymopentin, a synthetic pentapeptide derivative of thymopoietin, could enhance the protective effect of interleukin‐1α when both administered prior to sublethal irradiation in the C57BL/6 mouse. Thymopentin (10 mg/kg/day/7 days) was injected intraperitoneally in groups of C57BL/6 mice. Then, interleukin‐1α was administered on day 7. Twenty hr later, all groups were given whole body sublethal irradiation of 750 rad by 60Co elements. In some groups of mice, treatment with thymopentin was continued for 1 week after irradiation. Efficacy of the combination treatment was assessed by evaluation of mortality, as well as by histologic examination of the brain, testis, bone marrow, heart and spleen. The combination of relatively low doses of interleukin‐1α (700 U) with thymopentin yielded a survival which was nearly that observed with interleukin‐1α (1000 U) given alone (about 100%). The optimal effect was observed in animals treated for 15 days with thymopentin, either in combination or alone. In addition, incidence and severity of histological lesions were also lower in animals with the some treatment schedule. Our results suggest that the combined treatment thymopentin‐interleukin‐1α prevents radiation damage in the mouse.
Central and Peripheral Mediation of Hypothermia, Tremor and Salivation Induced by Muscarinic Agonists in Mice
Authors: Sánchez C. , Meier E.
Published: March 2009

Abstract:Hypothermia, tremor and salivation induced by muscarinic cholinergic agonists were studied in mice. Oxotremorine‐M (quarternary agonist) shows high potency after intracerebroventricular administration, but the potency is low after subcutaneous administration. Oxotremorine potency (non‐quarternary agonist) is higher after intracerebroventricular administration than after subcutaneous administration. Scopolamine and atropine (non‐quarternary antagonists) antagonize oxotremorine‐induced effects more potently after intracerebroventricular than subcutaneous administration. The quarternary antagonists N‐methylscopolamine (NMS) and N‐methylatropine (NMA) potently antagonize oxotremorine‐induced salivation after both subcutaneous and intracerebroventricular administration. Hypothermia is antagonized partially (20‐40%) over a large dose range after subcutaneous administration. Inex vivoreceptor‐binding studies of rat brain tissue, oxotremorine, scopolamine and atropine administered subcutaneously dose‐dependently displace3H‐oxotremorine‐M. Oxotremorine‐M and NMS displace3H‐oxotremorine‐M by 21% and 35%, respectively; NMA is ineffective. In conclusion: Muscarinic cholinergic‐mediated tremor is centrally regulated; hypothermia involves both a central and a peripheral component, the peripheral regulation being relatively less important than the central; central and peripheral regulation of salivation are equally important. Penetration of the blood brain barrier by oxotremorine‐M and NMS is shown in theex vivobinding studies.
Cardiovascular Haemodynamics of Oriental Hornet Venom Sac Extract
Authors: Rubin Yoram , Duvdevani Poriya , Ishay Jacob S.
Published: March 2009

Abstract: The effects of hornet venom sac extract on the functioning of the cardiovascular system was assessed in dogs by concomitant examination of the following parameters: Systemic blood pressure, blood pressure and the dp/dt derivative of the left ventricle of the heart, heart rate, direct measurement of the left ventricular wall thickness, cardiac output, and body temperature. The effect of adult hornet venom sac extract on the canine cardiovascular system was rapid and led to a sharp drop in the systemic blood pressure, a similar drop in the pressure and dp/dt derivative in the left ventricle, to bradycardia, immediate thickening of the left ventricular wall and to an immediate rise in the cardiac output. As for the canine temperature, this dropped immediately following the administration of venom sac extract and remained at the new low level for at least 30 min. The smaller molecular weight components (less than 10 kilodalton) in venom sac extract have been found to be responsible for the immediate effects of venom sac extract on the cardiovascular system. On the other hand the high‐molecular weight components exert more delayed effects which lead to a cumulative disturbance of cardiac function.
Effect of a Single Lethal Dose of TCDD on the Levels of Monoamines, their Metabolites and Tryptophan in Discrete Brain Nuclei and Peripheral Tissues of Long‐Evans Rats
Authors: Unkila Mikko , Tuomisto Jouni T. , Pohjanvirta Raimo , MacDonald Ewen , Tuomisto Leena , Koulu Markku , Tuomisto Jouko
Published: March 2009

Abstract: 2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin (TCDD) is one of the most potent anorexigens in rats with a yet unidentified mechanism of action. Since biogenic amines are known to essentially participate in the control of body weight and food intake, their levels were determined in various hypothalamic and other brain sites together with selected peripheral tissues after TCDD administration to adult male Long‐Evans rats. Rats were given a single lethal dose of TCDD (1000 μ/kg intraperitoneally, in dimethylsulphoxide) or vehicle alone and they were decapitated at 1, 5, 25 hr or 8 days after TCDD administration. The samples were analyzed for concentrations of biogenic amines and their metabolites by HPLC‐EC. Administration of TCDD increased the concentration of tryptophan at 8 days after exposure by about 20% in almost all nuclei examined, with the change reaching statistical significance in the lateral hypothalamic area and in lateral and medial accumbens nuclei. Importantly, this elevation was not seen in pair‐fed control animals. Although not statistically significant, there was a tendency to 5–10% diminished dopamine, serotonin and/or 5‐hydroxyindoleacetic acid levels in most brain sites during the first day postexposure. The present results argue against a crucial role for catecholamines as mediators of TCDD toxicity. However, the delayed changes in brain tryptophan do not appear to be secondary to TCDD hypophagia.
The Use and Handling of Acrylic Bone Cement in Danish Orthopaedic Departments
Authors: Darre Erik , Hölmich Per , Jensen Jørgen Steen
Published: March 2009

Abstract: In order to evaluate the use and handling of acrylic bone cement, questionnaires were presented to all Danish orthopaedic departments in 1987 and again in 1992. Marked improvements in the environmental safety precautions for handling of bone cement had taken place during the 5‐year period. In 1992, the intraoperative handling and use of bone cement is thus generally considered safe. Further improvements are still to be advocated in some departments. The exposure to methylmethacrylate monomer (MMA) vapour during the cementation procedures should be eliminated by local punctual field suction or change to a bone cement with a lower content of monomer (MMA/n‐decylmethacrylate/isobornylmethacrylate bone cement). Unnecessary manual contact with the cement should be avoided, and if contact is necessary, special protective gloves (butyl rubber gloves or 4H‐gloves$rG) should be used in addition to ordinary surgical gloves.
Effects of Tylosin on the Pituitary‐Gonadal Axis in Male Rats
Authors: Meisel M. L. , Winterhoff H. , Jekat F.‐W.
Published: March 2009

Abstract:Former investigations in rats showed a decrease of thyroid hormone concentrations after treatment with the antibiotic and growth promoter tylosin (Schäfer 1984). In the present study, the effects of tylosin on the pituitary‐gonadal axis in adult rats were studied. The substance was administered in two concentrations to rats (0.1 and 5.0 mg tylosin/kg feed) for three different periods: 15, 29 and 65 days. At the end of each period the organ weights were determined and the hormone levels in serum and pituitary gland were measured by radioimmunoassay. After 15 days reduced levels of LH (luteinizing hormone) and FSH (follicle stimulating hormone) in the pituitary gland and LH in serum were found. Moreover, the weight of seminal vesicles was decreased and the weight of pituitary increased. After 29 days an equilibrium between effects of tylosin and endocrine contraregulation seemed to be achieved. The prolonged tylosin administration (65 days) depressed testosterone concentration and increased hypophyseal LH stores. The testing of the pituitary‐testicular axis with acute LHRH (luteinizing hormone‐releasing hormone) stimulation caused a reduced increse of LH in animals treated with 0.1 mg tylosin. In contrast, the LH responsiveness to LHRH in animals treated with 5.0 mg tylosin was unchanged, while the testosterone response to released LH was reduced. These findings demonstrate that tylosin acts on the pituitary as well as on peripheral functions of the pituitary‐gonadal‐axis and that its effect depends on the time interval of tylosin administration.
Cancer Etiology: Agents Causally Associated with Human Cancer
Authors: Vainio Harri , Wilbourn Julian
Published: March 2009

Abstract: Cancer is a multifactorial and multistage process, the exact mechanisms of which are still only partially known. However, even in the absence of a complete understanding of the process of carcinogenesis, we have been able to identify several factors which modify the risk of tumour development in humans. These include both endogenous and environmental factors, ranging from exposure to a single identified chemical to the occupations we follow in order to make our living. Cancer prevention strategies may differ in different parts of the world. In Europe, lung cancer is responsible for about one fourth of all cancer deaths and most of it could be prevented by eliminating tobacco smoking. Other exposures that can be controlled include occupational exposures to agents known to cause cancer at sites such as lung, bladder, paranasal sinuses, leukaemia, lymphoma and liver, as well as exposure to sunlight, known to be associated with both non‐melanocytic and melanocytic skin cancer. Liver cancer is a common cancer in other regions of the world where hepatitis B virus (HBV) infection is endemic; in these areas, fungal contamination of food is also common. While immunization against HBV may be the method of choice in the long run, reduction of exposure to aflatoxins might be a more useful intermediate goal in primary prevention because of the strong interaction between hepatitis B and aflatoxin exposure on liver cancer risk. To date, few chemical agents have been proved to be of etiological relevance to cancer in humans at sites such as the breast (with the exception of oestrogenic hormones), ovary, colon‐rectum and prostate. Therefore, imaginative new approaches are needed to study the etiology of and prevention for these common cancers.
The Concept of Multifactorial Etiology of Cancer
Authors: Olsen Jørn , Overvad Kim
Published: March 2009

Abstract: The concept of causes is not just for professional philosophers to discuss. The epidemiologists also have to clarify how the concept is used since its meaning has profound implications for understanding basic measures of exposure‐disease association. The concept of cause also has importance when designing a study or when analyzing epidemiological data.

The paper describes the components cause model and its relationship with the mechanism of disease action. A measure of interaction is also presented which is based upon the components cause model. The common sense concept of causes also plays a fundamental role for the success of a health preventive programme according to the Health Belief Model. The component cause model may clarify causal patterns in situations when only a few of the exposed get the disease which the programme tends to prevent.
Cancer‐Protective Factors in Fruits and Vegetables: Biochemical and Biological Background.
Authors: Dragsted Lars Ove , Strube M. , Larsen J. C.
Published: March 2009

Abstract: Cancer‐protective factors are present in several fruits, vegetables and commonly used spices and herbs. They can be divided into several different groups, based on their chemical structure, e.g. polyphenols, thiols, carotenoids and retinoids, carbohydrates, trace metals, terpenes, tocopherols and degradation products of glucosinolates (i.e. isothiocyanates, indoles and dithiothiols) and others. Among each of these groups of compounds are substances, which may exert their cancer‐protective action by more than one biochemical mechanism.

The biochemical processes of carcinogenesis are still not known in detail and probably varies with the cancer disease in question. Accordingly, the description of the biochemical backgrounds for the actions of cancer‐protective factors must be based on a simplified model of the process of carcinogenesis. The model used in this presentation is a generalised initiation‐promotion‐conversion model, in which initiators are thought to be directly or indirectly genotoxic, promoters are visualised as substances capable of inferring a growth advantage on initiated cells and converters are believed to be genotoxic, e.g. mutagens, clastogens, recombinogens or the like.

Experimental evidence for the mechanisms of action of cancer‐protective agents in fruits and vegetables that protect against initiation include the scavenging effects of polyphenols on activated mutagens and carcinogens, the quenching of singlet oxygen and radicals by carotenoids, the antioxidant effects of many compounds including ascorbic acid and polyphenols, the inhibition of activating enzymes by some flavonols and tannins, the induction of oxidation‐and of conjugation (protective) enzymes by indoles, isothiocyanates and dithiothiones, the shielding of sensitive structures by some polyphenols and the stimulation of DNA‐repair exerted by sulphur‐containing compounds.

Mechanisms at the biochemical level in anti‐promotion include the antioxidant effects of carotenoids and the membrane stabilizing effects reported with polyphenols, the inhibition of proteases caused by compounds from soybeans, the stimulation of immune responses seen with carotenoids and ascorbic acid and the inhibition of ornithine decarboxylase by polyphenols and carotenoids.

A few inhibitors of conversion have been identified experimentally, and it can be argued on a theoretical basis, that many inhibitors of initiation should also be efficient against conversion.

The mechanisms of anticarcinogenic substances in fruits and vegetables are discussed in the light of cancer prevention and inhibition.
General Preventive Measures Against Carcinogenic Exposure in the External Environment
Authors: Keiding Lis M.
Published: March 2009

Different measures are used to prevent unacceptable carcinogenic exposure from different sources in the external environment, be it accumulated carcinogens from previous pollution, exposure related to life‐style, and exposure related to living standards and the organization of the community as a whole. A precondition for goal‐directed prevention is knowledge of exposures to carcinogens and measures to minimize or substitute carcinogens in products and in emissions. One of the most significant sources of carcinogens in the outdoor air in many Western countries is the traffic, especially diesel‐powered vehicles. Necessary preventive measures include restriction of carcinogenic exhaust from the individual vehicle, plans for the community to diminish transportation needs, as well as to changing the usual behaviour of the individual. Unlike exposure to carcinogens in the surrounding air, exposure to accumulated carcinogens in ground‐water and in soil at polluted sites may be diminished by the pattern of use. International aspects are involved in for instance minimizing the risk of getting skin cancer from sunlight. Besides protecting vulnerable individuals there should be a global preservation of the ozone layer. Lowering the risk of long transported air pollution, like radioactivity from accidents at nuclear power stations, demands international efforts to increase safety measures and information about accidents.
Dietary Guidelines and Food Recommendations in Denmark
Authors: Haraldsdóttir Jóhanna
Published: March 2009

In Denmark the official dietary guidelines and food recommendations are expressed in the Five Dietary Advices and the Danish food circle. Such guidelines are entirely different from recommendations on nutrient intakes, which are expressed in terms of exact values and established through a more formal procedure.

Some of the most fundamental principles for food recommendations given to the public are that they are perceived as consistent and based on a firm consensus, and that their relevance and translation into practical action is obvious to the public. When the situation in Denmark is compared to these principles the main issue turns out to be neither lack of consistency in recommendations issued by government agencies and voluntary health organisations, nor is it lack of consensus among the experts about the fundamental messages of the guidelines. A more important problem is that the public does not distinguish between formal recommendations from authorized sources, and a variety of advices from other sources as well as non‐formal comments from individual scientists. A cause of serious concern is the fact that the Danish public seems to lack a realistic picture of what the dietary guidelines imply in terms of foods. A number of contradictions is built into the process of communicating dietary recommendations effectively to the public. These can only be solved if the process is planned on a long‐term basis.
Calcium Antagonistic Properties of the Sesquiterpene T‐Cadinol and Related Substances: Structure‐Activity Studies
Authors: Zygmunt P. M. , Larsson B. , Sterner O. , Vinge E. , Högestätt E. D.
Published: March 2009

The calcium antagonistic properties of (+)‐T‐cadinol, some of its stereoisomers and related terpenes were investigated in both functional and radioligand binding studies, and the effects were compared with those of the dihydropyridine calcium antagonist (±)‐nimodipine. In the isolated rat aorta, the terpenes relaxed contractions induced by 60 mM K+more potently than those induced by phenylephrine. (+)‐T‐cadinol and its stereoisomers were the most potent among the terpenes to relax K+‐induced contractions, whereas they were approximately 10,000 times less potent than (±)‐nimodipine in this regard. Binding of the dihydropyridine radioligand [3H]‐(+)‐PN200‐110 was studied on rat cerebral cortical membranes. Displacement and saturation studies indicated that (+)‐T‐cadinol caused a competitive inhibition of binding. The log Kivalues for (+)‐T‐cadinol and (±)‐nimodipine from displacement studies (−4.7 and −9.2) corresponded with the log RC50values for relaxation of K+‐contracted rat aortas (−5.0 and −9.0). For the terpenes, there was a significant correlation (P<0.001, rs= 0.89) between displacement of dihydropyridine binding and the ability to relax K+‐induced contractions. The structures of three terpenes were chemically modified by blocking hydroxyl groups. The potency of these derivatives, as well as the naturally occurring derivative 2‐oxo‐T‐cadinol, to relax K+‐induced contractions was not correlated to the lipophilicity of the compounds. Instead, other qualities appear to be of importance for the functional effects. Our results suggest that (+)‐T‐cadinol and related terpenes may represent a new chemical class of calcium antagonists, which interact with dihydropyridine binding sites on the voltage‐operated calcium channels.
Oxysterols Inhibit Gap Junctional Communication between Rat Hepatocytes in Primary Culture
Authors: Guo Xinbiao , Ohno Yasuo , Miyajima Atsuko , Sunouchi Momoko , Takanaka Akira
Published: March 2009

Several oxysterols were examined for their effect on gap junctional communication between rat hepatocytes in primary culture. 25‐Hydroxycholesterol, 22(S)‐hydroxycholesterol and 7β‐hydroxycholesterol, in decreasing order of potency, markedly inhibited gap junctional communication. In contrast, 7‐ketocholesterol showed no inhibitory effect. The inhibition of gap junctional communication by oxysterols was not a consequence of changes in cell viability, as measured by lactate dehydrogenase leakage and 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) reduction activity. The addition of exogenous cholesterol to the culture medium did not abolish the effect of 25‐hydroxylcholesterol, suggesting that the capacity of oxysterols to inhibit gap junctional communication is independent of their inhibitory effect on cholesterol synthesis. We suppose that inhibition of gap junctional communication may be an early sign of oxysterols‐induced toxicity on hepatocytes.
Prenatal Toxicity of Xylene Inhalation in the Rat: A Teratogenicity and Postnatal Study
Authors: Hass Ulla , Jakobsen Bodil M.
Published: March 2009

Technical xylene (cas.nr. 1330‐20‐7) was investigated for development toxicity in a teratology and in a postnatal study. Rats (Mol: WIST) were exposed to 500 p.p.m. 6 hr per day on days 4 to 20 of gestation. There were no signs of maternal toxicity. In the teratology study, no exposure‐related differences were found except for delayed ossification of os maxillare. In the postnatal study, the xylene‐exposed pups had a higher body weight and an impaired performance on a motor ability test (Rotarod). Due to the possibility of direct toxic effects of xylene on the developing central nervous system, further studies are needed to investigate dose‐effect relationship for this type of effects.
Inhibition of Human Neutrophil Actin Polymerization, Phagocytosis and Oxidative Burst by Components of Decongestive Nosedrops
Authors: Bjerknes Robert , Steinsvåg Sverre Karmhus
Published: March 2009

Human neutrophil functions have been examined after exposure of leukocytes to components of decongestive nosedrops in vitro. Both the vasoactive components oxymethazoline chloride and xylomethazoline chloride, as well as the preservative benzalkonium chloride, showed a concentration‐ and time‐dependent deleterious effect on neutrophil actin polymerization, phagocytosis and oxidative burst. The most toxic of the drug components was benzalkonium chloride, which in the commercial nosedrops tested was present in concentrations about 20 times higher than that compatible with intact neutrophil functions. These findings suggest possible inhibition of mucosal neutrophil activity following exposure to nosedrops in vivo, and support earlier reports that have questioned the use of preservatives in decongestive nosedrops.
Reproducibility over Time of Mephenytoin and Debrisoquine Hydroxylation Phenotypes
Authors: LLerena Adrián , Valdivielso Maria J. , Benítez Julio , Bertilsson Leif
Published: March 2009

Mephenytoin and debrisoquine hydroxylation phenotypes were determined twice in 15 Spanish healthy volunteers with an interval of about one year. The phenotype assignment did not change in any subject for either debrisoquine or mephenytoin. Among extensive metabolisers of mephenytoin, there was a slight increase (P = 0.04) of the mephenytoin‐S/R enantiomeric ratio over the study period. The family members of a poor metaboliser of mephenytoin were phenotyped, and the heterozygous extensive metabolisers were found to have higher mephenytoin‐S/R ratios than other extensive metabolisers suggesting a correlation between the genotype and the S/R ratio.
Effects of Aging on Acute Toxicity of Nicotine in Rats
Authors: Okamoto Masato , Kita Taizo , Okuda Hirotsugu , Tanaka Takeshi , Nakashima Toshikatsu
Published: March 2009

Abstract:Acute toxicity of nicotine was examined in old (24 months) and young (6 weeks) Wistar rats. There were no significant age differences in the mortality and convulsive responses induced by an intraperitoneal injection of nicotine (24.5 mg/kg). The lethal nicotine levels in blood and cortex and the latent period to death in old rats were larger than those in young rats. Cortical and blood nicotine levels 15 min. after the nicotine injection in old rats were also higher than those in young rats. Nicotine significantly increased dopamine, 3,4‐dihydroxyphenylacetic acid and homovanillic acid levels in striatum and hippocampus in young rats, but not those in old rats. Moreover, nicotine‐induced elevations in blood levels of corticosterone in old rats were also less than those in young rats. On the other hand, the cytochrome P‐450 content, the nicotine oxidase activity and the flavin‐containing monooxygenase activity in liver showed age‐related decreases in the young, the middle‐aged (12 months) and the old rats. These results indicate that the acute toxicity of nicotine in old rats reflects the decreases in hepatic nicotine metabolism and in brain sensitivity to nicotine.
Effects of Divalent Cations on Adenosine Agonist Binding to A1 Receptors and Non‐A1/Non‐A2 Sites in Rat Cerebral Cortex
Authors: Traversa Ugo , Rosati Anna M. , Florio Chiara , Vertua Rodolfo
Published: March 2009

Abstract:In the present study results are reported concerning the effects of several divalent cations on the binding characteristics of [3H]‐cyclohexyladenosine on A1 adenosine receptors and of [3H]‐N‐ethylcarboxamidoadenosine on non‐A1/non‐A2 sites in membranes from cerebral cortex of the rat. The [3H]‐cyclohexyladenosine binding to A1 receptors was dose‐dependently increased by Mn2+, Co2+, Ca2+. The binding characteristics of the agonist were differently affected by Ca2+/Mn2+and Mg2+. Ca2and Mn2+increased the Bmaxvalue without any change in Kd, whereas Mg2+decreased the Kdvalue without changing the Bmax. In the presence of Ca2+and Mg2+the Kdvalue was similar to that obtained in the presence of Mg2+, whereas the Bmaxvalue was similar to the apparent number of binding sites calculated in the presence of Ca2+. The cations, Cu2+, Cd2+, Zn2+, decreased the Al binding with IC50, values of 19.6 μM, 39.2 μM and 103.9 μM, respectively. The binding characteristics of [3H]‐N‐ethylcarboxamidoadenosine to non‐A1/non‐A2 sites were affected by Ca2+, Mn2+, Co2+and Mg2+in the opposite manner to A1 receptors. They decreased the binding with IC50values of 20.1 mM, 22.8 mM, 93.0 mM and 18.1 mM, respectively. This occurs through an enhancement in Kd, values without changes in the number of binding sites. The findings on A1 receptor and non‐A1/non‐A2 binding site, taken together, suggest that cations could also exert a modulatory action via specific interactions with divalent cation binding sites on the receptor molecule.
Dose and Regimen Effects of Poly ICLC, an Interferon Inducer, in a Multi‐Dose Bleomycin Model of Interstitial Pulmonary Fibrosis*
Authors: Wild James S. , Hyde Dallas M. , Giri Shri N.
Published: March 2009

Abstract: The antifibrotic effects of an interferon inducer, polyinosinic‐polycytidylic acid complexed with poly‐L‐lysine (poly ICLC), was evaluated in a bleomycin‐hamster model of pulmonary fibrosis. Hamsters received three consecutive intratracheal doses of bleomycin (2.5, 2.0, and 1.5 U/kg/5 ml) or saline at weekly intervals. Poly ICLC at three doses (0.5, 1.0, and 1.5 mg/kg body weight) or saline was injected intraperitoneally by daily and semiweekly regimens for four weeks, and animals were sacrificed at five weeks. In both the daily and semiweekly poly ICLC regimens, hamsters receiving bleomycin plus poly ICLC demonstrated increased mortality and decreased weight gain compared to the vehicle and bleomycin control groups. The groups receiving bleomycin plus daily poly ICLC demonstrated poly ICLC‐dose related effects for weight changes, lung hydroxyproline and lung prolyl hydroxylase activity. Depending on the poly ICLC dose, bleomycin plus daily poly ICLC produced significantly decreased hydroxyproline or significantly increased hydroxyproline and prolyl hydroxylase activity compared to the bleomycin control group. In contrast, the groups receiving bleomycin plus semiweekly poly ICLC did not demonstrate poly ICLC‐dose related effects or significant differences from the bleomycin control group for any of the biochemical assays performed. The results of this study indicate that, depending on dose and regimen, poly ICLC can reduce collagen accumulation or produce a synergistic toxicity when administered with multiple doses of bleomycin. The toxic effects may restrict the therapeutic potential of poly ICLC in combination with bleomycin for anticancer therapy.
Stimulation‐Dependent Effect of Antiepileptic Drugs in Amygdala Kindled Rats on Both Seizure Score and Duration of Afterdischarges
Authors: Voits Mechthild , Frey Hans‐Hasso
Published: March 2009

Abstract:The ED50for abolition of generalized seizures and reduction of afterdischarges to 20% of the control duration was determined in kindled rats for phenobarbital, carbamazepine, phenytoin, valproic acid, clonazepam, and diazepam, both at a stimulation intensity of 200 μA and at 10 μA above the threshold for generalized seizures (threshold stimulation). Phenobarbital, carbamazepine, and valproic acid acted in a stimulus‐dependent manner, i.e. the ED50was higher at 200 μA than at threshold stimulation. Phenytoin had the same ED50irrespective of the stimulus intensity. Generalized seizures and afterdischarges were suppressed by the same doses of the drugs mentioned. The benzodiazepines, clonazepam and diazepam, had a differential effect: they suppressed generalized seizures at low doses, whereas afterdischarges were only suppressed incompletely at relatively high doses. The ED50of both benzodiazepines was independent of stimulus intensity. In order to avoid erroneous conclusions a standardization of kindling parameters, especially stimulation intensity, is proposed when drug effects are to be compared.
Pharmacology of Morphine and Morphine‐3‐glucuronide at Opioid, Excitatory Amino Acid, GABA and Glycine Binding Sites
Authors: Bartlett Selena E. , Dodd Peter R. , Smith Maree T.
Published: March 2009

Abstract:Morphine in high doses and its major metabolite, morphine‐3‐glucuronide, cause CNS excitation following intrathecal and intracerebroventricular administration by an unknown mechanism. This study investigated whether morphine and morphine‐3‐glucuronide interact at major excitatory (glutamate), major inhibitory (GABA or glycine), or opioid binding sites. Homogenate binding assays were performed using specific radioligands. At opioid receptors, morphine‐3‐glucuronide and morphine caused an equipotent sodium shift, consistent with morphine‐3‐glucuronide behaving as an agonist. This suggests that morphine‐3‐glucuronide‐mediated excitation is not caused by an interaction at opioid receptors. Morphine‐3‐glucuronide and morphine caused a weak inhibition of the binding of3H‐MK801 (non‐competitive antagonist) and125I‐ifenprodil (polyamine site antagonist), but at unphysiologically high concentrations. This suggests that CNS excitation would not result from an interaction of morphine‐3‐glucuronide and high‐dose morphine with these sites on the NMDA receptor. Morphine‐3‐glucuronide and morphine inhibited the binding of3H‐muscimol (GABA receptor agonist),3H‐diazepam and3H‐flunitrazepam (benzodiazepine agonists) binding very weakly, suggesting the excitatory effects of morphine‐3‐glucuronide and high‐dose morphine are not elicited through GABAA, receptors. Mor‐phine‐3‐glucuronide and high‐dose morphine did not prevent re‐uptake of glutamate into presynaptic nerve terminals. In addition, morphine‐3‐glucuronide and morphine did not inhibit the binding of3H‐strychnine (glycine receptor antagonist) to synaptic membranes prepared from bovine spinal cord. It is concluded that excitation caused by high‐dose morphine and morphine‐3‐glucuronide is not mediated by an interaction with postsynaptic amino acid receptors.
Cardiotoxicity of Doxorubicin: Effects of Drugs Inhibiting the Release of Vasoactive Substances
Authors: Rossi F. , Filippelli W. , Russo S. , Filippelli A. , Berrino L.
Published: March 2009

Abstract:The therapeutic usefulness of doxorubicin, an antineoplastic drug, is limited by its cardiotoxicity whose mechanism is as yet unknown. Several hypotheses have been postulated including also the release of vasoactive substances, so the aim of the present investigations was to study the relationship between the release of vasoactive substances and the development of doxorubicin‐induced cardiotoxicity. The effects of the following drugs on doxorubicin‐induced (cumulative dose of 20 mg/kg intraperitoneally) cardiotoxicity in rats have been evaluated: verapamil (1 and 10 mg/kg orally), that inhibits the slow channel influx of calcium and catecholamine release, acetylsalicylic acid (50 and 100 mg/kg orally), that inhibits the prostaglandin biosynthesis and release, and cromolyn sodium (cromolyn; I and 10 mg/kg orally), that inhibits the secretion of histamine. Our results showed that verapamil reduced and delayed doxorubicin‐induced mortality, and limited doxorubicin‐induced body weight decrease and ECG changes. Acetylsalicylic acid and cromolyn did not protect against doxorubicin‐induced cardiotoxicity. These findings suggest that the release of vasoactive substances does not play a prevalent role in the development of doxorubicin‐induced cardiotoxicity. The protective effect of verapamil is probably due to the inhibition of doxorubicin‐induced intracellular calcium overload.
Studies on Urinary Proteoglycan Excretion in Occupational Cadmium Exposure
Authors: Savolainen H.
Published: March 2009

Abstract: Six foundrymen occupationally exposed to cadmium fumes excreted in random urine samples 4.8 + 2.9 pg cadmium/g creatinine (± S.D.). Six controls excreted 0.15 ± 0.09 pgig creatinine (± S.D.). The excretion of glycosaminoglycans by exposed men (2.3 ± 1.1 mg/mmol creatinine, ± S.D.) did not differ from that of controls (2.3 ± 1.6 mg/mmol, ± S.D.). However, electrophoretic analysis of the isolated urinary proteoglycan fraction revealed a dose‐dependent progressive increase in the intensity of two bands with a molecular weight between 45,000 and 50,000. In control urines and in samples with urinary cadmium less than 3 μg/g creatinine, only one major band with a molecular weight of 100,000 was detected. The changes may serve as early indicators of the harmful effects of cadmium on the proteoglycan‐containing barriers of the nephron.
Local Anaesthetic Bupivacaine Alters Function of Sarcoplasmic Reticulum and Sarcolemmal Vesicles from Rabbit Masseter Muscle
Authors: Takahashi Shun‐suke
Published: March 2009

Abstract:The effects of local anaesthetics, bupivacaine and lidocaine, on Ca2+flux behaviour of sarcoplasmic reticulum and on sarcolemmal functions were studied in the rabbit masseter muscle. The experiments were performed on sarcoplasmic reticulum and sarcolemmal vesicles prepared at 1 to 10 days after injection of local anaesthetics or saline into masseter muscle as well as on sarcoplasmic reticulum vesicles prepared from non‐treated rabbits (for assessment of the effect onin vitroincubation with local anaesthetics). Bupivacaine potently reduced the efficiency of active sarcoplasmic reticulum Ca2+transport as evaluated by coupling ratio (Ca2+transported/ATP hydrolyzed, in the presence of oxalate) at 3 days after the injection; there was only a slight degree of uncoupling of Ca2+transport from ATP hydrolysis with lidocaine injection. Bupivacaine but not lidocaine, at 3 days after injection, decreased both the apparent permeability of sarcoplasmic reticulm vesicles to Ca2+, determined by measuring net efflux of Ca2+after stopping pump‐mediated fluxes, and the steady‐state Ca2+load in sarcoplasmic reticulum, but had no effect on overall turnover of the Ca2+ATPase. The effects of bupivacaine on apparent sarcoplasmic reticulum Ca2+permeability and steady‐state Ca2+load were inhibited by a Ca2+antagonist verapamil. The reduction of Ca2+uptake of sarcoplasmic reticulum and the protective effect of verapamil were reproduced in unfractionated homogenates prepared at 3 days after bupivacaine injection.In vitroexposure of sarcoplasmic reticulum vesicles to bupivacaine (0.5 to 50 mM) reduced steady‐state Ca2+load in a dose‐dependent manner. The observed effect elicited by bupivacaine (25 mM) was partially protected by procaine, an inhibitor of Ca2+‐induced Ca2+release from sarcoplasmic reticulum, or by specific closure of the sarcoplasmic reticulum Ca2+release channel by ryanodine, suggesting the possibility thatin vitroexposure of sarcoplasmic reticulum vesicles to bupivacaine may produce an increase in apparent permeability of sarcoplasmic reticulum to Ca2+. In sarcolemma, bupivacaine reduced Na+,K+‐ATPase and Na+‐Ca2+exchange activities at 3 days after injection; the effects on sarcolemmal vesicles were prevented by verapamil. These results suggest that although the effects elicited by bupivacaine injection and thein vitroexposure to bupivacaine on steady‐state Ca2+load of sarcoplasmic reticulum vesicles were similar, the membrane properties of the vesicles from bupivacaine‐treated masseter muscles and those from normal untreated muscles may not be the same, which indicates that pure bupivacaine effect is due partly by an effect on ryanodine‐ and procaine‐sensitive Ca2+channels. It is also postulated that the effect of bupivacaine, when injected into masseter muscle, may partly be linked to increased influx of Ca2+through verapamil‐sensitive Ca2+channels localized in the cell membrane.
Uptake of Nicotine in Hair During Controlled Environmental Air Exposure to Nicotine Vapour: Evidence for a Major Contribution of Environmental Nicotine to the Overall Nicotine Found in Hair from Smokers and Non‐Smokers
Authors: Nilsen Turid , Zahlsen Kolbjørn , Nilsen Odd G.
Published: March 2009

Abstract:Hair from smokers and non‐smokers has been exposed in a dynamic exposure chamber to air nicotine concentrations ranging from 1.5 to 45 and from 20 to 2000 μg/m3for 8 weeks and 72 hr, respectively. Accumulated hair nicotine was quantified by GC/MS. Hair was also collected for direct measurements of nicotine in 0‐2, 2‐4 and 4‐6 cm segments from the scalp. Human hair showed a high affinity for air nicotine and the chamber experiments revealed a linear relationship between the initial hair uptake rates of nicotine and the duration of exposure at all air nicotine concentrations applied. Hair nicotine uptake rate decreased with time after 4 to 6 weeks exposure to 15 and 45 μg/m3air concentrations of nicotine, but not to the 1.5 μg/m3nicotine concentration. Ratio between the hair uptake rate of nicotine and the applied air concentration of nicotine decreased with increasing air concentrations of nicotine. Segment analysis of hair revealed an outward increasing gradient of nicotine in hair. Hair uptake pattern of air nicotine suggests the uptake to be governed by an equilibrium between nicotine in air and nicotine on the hair surface, possibly combined with a slower diffusion process of nicotine from the hair surface into the hair core. The hair segment analysis of nicotine indicates that environmental nicotine is the dominating contributor to the overall nicotine found in hair both from smokers and non‐smokers.
Changes in Caffeine, Lidocaine and Trimethadione Metabolism in Carbon Tetrachloride‐Intoxicated Rats as Assessed by a “Cocktail” Study
Authors: Tanaka Einosuke , Ishikawa Akio , Misawa Shogo
Published: March 2009

Abstract:We investigated the possibility of predicting liver damage from changes in the serum concentrations of caffeine (10 mg/kg), lidocaine (4 mg/kg) and trimethadione (4 mg/kg), which are metabolized catalysed by different cytochrome P450 (P450) and/or are dependent on blood flow, in rats with carbon tetrachloride (CCl4: 0.25 ml/kg)‐induced liver injury using a strategy referred to as a “cocktail” study. These 3 probe drugs were simultaneously administered intravenously. The half‐lives (t1/2) of caffeine, lidocaine and trimethadione were significantly longer in the CCl4‐treated group than in oil‐treated controls, but no significant differences were observed in mean apparent volumes of distribution (Vd). Serum total body clearance (CL) values of all three drugs were markedly reduced in CCl4‐treated animals. In rats with liver damage, the production of 3 metabolites (theobromine, paraxanthine and theophylline) of caffeine in addition to the only metabolite (dimethadione) of trimethadione after intravenous administration of probe drugs were significantly reduced compared to those of controls. These findings suggest that each probe drug, metabolized by different or partially overlapping P450, is useful in evaluating drug‐oxidizing capacity in liver disease.
Alterations of Lidocaine and Pentylenetetrazol‐Induced Convulsions by Manipulation of Brain Monoamines
Authors: Abed Wadie T.
Published: March 2009

Abstract: The tresholds for pentylenetetrazol and lidocaine‐induced clonic convulsions were significantly influenced by manipulation of brain biogenic amines. Pretreatment with inhibitors of monoamine synthesis, α‐methyl‐p‐tyrosine and p‐chlorophenylalanine, caused significant decreases in brain monoamine contents and pentylenetetrazol seizure threshold, while the threshold for lidocaine‐induced convulsions was significantly increased by either treatment. Moreover, the inhibitor of dopamine‐β‐hydroxylase, disulfiram, caused significant decrease in brain noradrenaline (NA) and significant increase in brain dopamine (DA) contents. The threshold for pentylenetetrazol‐induced convulsions was decreased by treatment with disulfiram, while that of lidocaine was increased by the same treatment. Furthermore, treatment with L‐dihydroxyphenylalanine (L‐DOPA) caused significant increase in brain DA contents, while 5‐hydroxytryptophan (5‐HTP) treatment caused significant increase in brain 5‐hydroxytryptamine (5‐HT) contents, but the thresholds for lidocaine and pentylenetetrazol‐induced convulsions were not influenced by either treatment. These results may suggest that the brain monoaminergic systems, different from their ability to inhibit control of pentylenetetrazol seizures, act to potentiate lidocaine‐induced convulsions.
Assay of Linuron and a Pesticide Mixture Commonly Found in the Italian Diet, for Promoting Activity in Rat Liver Carcinogenesis
Authors: Pasquini Rossana , Scassellati‐Sforzolini Giuseppina , Dolara Piero , Pampanella Lucia , Villarini Milena , Caderni Giovanna , Fazi Marilena , Fatigoni Cristina
Published: March 2009

Abstract: The herbicide linuron and a mixture of 15 pesticides commonly found in the Italian diet have been assayed for promoting activity in rat liver carcinogenesis. Composition of the pesticide mixture was: henomyl (19.55%); dithiocarbamates (20.67%); thiabendazole (14.94%); diphenylamine (14.25%): chlorthalonil (13.13%); procymidone (7.96%); fenarimol (1.95%); chlorpropham (0.70%); vinchlozolin (0.28%); methidathion (2.37%); chlorpyriphos‐ethyl (2.09%); para‐thionmethyl (1.00%); chlorfenvinphos (0.27%); parathion (0.70%); pyrimiphos‐ethyl (0.14%). To determine promoting activity we evaluated induction of preneoplastic foci in diethylnitrosamine‐initiated hepatocytes, by positive gammaglutamyl‐transpeptidase (GGTase) staining in liver slides, and peroxisome proliferation by peroxisomal‐dependent catalase and palmitoyl‐CoA‐oxidase dosage. For the assay, groups of male Sprague‐Dawley rats were initiated with 100 mg/kg diethylnitrosamine intraperitoneally and, one week later, given 150 mg/kg/day linuron or 10 mg/kg/day pesticide mixture, administered by gavage three days a week. All rats were 2/3 hepatectomized at the beginning of the 3rd week. All treatments were terminated at the end of the 8th week, and the rats were sacrificed one week later. No significant increases in number and area (mm2) per slide unit area (cm2) of GGTase‐positive foci could be observed in linuron‐treated rats (5.84 ± 62/cm2; 0.139 ± 0.041 mm2/cm2) with respect to controls only initiated with diethylnitrosamine (4.47 ± 1.30/cm2; 0.182 ± 0.078 mm2/cm2). After treatment with the pesticide mixture, the number of preneoplastic foci was instead significantly increased (6.91 ± 2.05/cm2) although the area was not (0.188 ± 0.128 mm2/cm2). Moreover, no increases in the peroxisome proliferation enzymatic markers were observed in either treated groups. The results imply a possible carcinogenic risk for the population stemming from promoting activities of pesticide mixtures.