bluuebunny/crossref_metadata_2025 huggingface dataset:
Frequency of Acute Adverse Events to a Non‐Ionic Low‐Osmolar Contrast Medium: The Effect of Verbal Interview
Authors: Thomsen Henrik S.
Published: March 2009

Abstract: The effect of a standardized verbal interview on the frequency of reported adverse events to an intravenous injection of a non‐ionic low‐osmolar magnetic resonance (MR) contrast medium was studied during a low noise (low anxiety) magnetic resonance imaging (MRI) examination. During a 26‐month period 863 patients had an intravenous bolus (<10 sec.) injection of either 0.1 mmol/kg b.wt. or 0.3 mmol/kg b.wt. gadodiamide, were examined in 0.1 Tesla (T) MRI unit. All patients received written information about the examination, but no specific information about possible adverse events to the contrast medium. During the first 15 months, 479 patients were asked after the examination by the same radiographer the following question "Did you feel anything in relation to or after the contrast medium injection?". If the answer was affirmative, the patient was asked to specify the experience. During the subsequent 11‐month period, 384 patients had no interview about whether they felt anything in relation to the contrast medium injection. Only 9 out of 863 patients reported an adverse event and they all belonged to the group, which was interviewed. In 8 cases the adverse events lasted less than 5 min. The ninth patient had an attack of migraine 20 min. after the injection of the contrast medium. In one of the patients, who experiencied nausea, it was necessary to postpone scanning for 2 min. Two of the 9 adverse events were considered to be unrelated to the contrast medium. None of the 121 patients receiving the triple dose reported an adverse event. The frequency of reported adverse events depends on whether this information is obtained by active questioning. All reported adverse events were clinically mild and no dose‐response effect was observed.
Effect of Bile Acids on Hepatobiliary Transport of Cisplatin by Perfused Rat Liver
Authors: Villanueva G. R. , Mendoza M. E. , El‐Mir M. Y. , Monte M. J. , Herrera M. C. , Marin J. J. G.
Published: March 2009

Abstract:The liver and kidney collaborate in the excretion of the cytostatic drug, cis‐diamminedichloroplatinum(II) (cisplatin) from the body. Enhancement of this procces is envisaged as a way of reducing cisplatin toxicity, thus allowing increases in the doses administered. In this sense, using different compounds, several attempts have been made to enhance cisplatin biliary excretion. In this study, the ability of endogenous compounds belonging to the bile acid family to improve cisplatin excretion by the isolated perfused rat liver was investigated. A highly choleretic bile acid (ursodeoxycholic acid) and two others bile acids with marked micelle‐forming properties (glycocholic acid and chenodeoxycholic acid) were chosen for study. When these drugs were given at concentrations (1 μM) that did not affect the viability of liver preparations, a correlation between the biliary excretion of platinum and bile acid output was found. This was not due to the incorporation of cisplatin into mixed micelles because no correlation between the biliary output of lecithin or cholesterol and platinum was observed. Moreover, a wash‐out effect of bile acids was probably not the cause of bile acid‐induced platinum output into bile because no correlation between this and bile flow was found. An enhancement in cisplatin transport processes by the hepatocyte or by direct binding of cisplatin to bile acid monomers or aggregates cannot be ruled out. In spite of the biliary induction of cisplatin output, the net excretion of platinum was reduced under bile acid administration. This was related to lower platinum contents in the liver tissue, probably due to an inhibition of the ability of the hepatocyte to take up and/or retain cisplatin while subject to bile acid infusion. In summary, our results indicate that bile acids reduce the net excretion of cisplatin by the liver even though they induce an enhancement in the transport of this compound from the hepatocyte into bile.
The Effect of Amiloride and Sodium Chloride on Rat Renal and Hepatic 11β‐Hydroxysteroid Dehydrogenase Activities
Authors: Niepel Tanja , Maser Edmund , Hermans J. J. Rob
Published: March 2009

Abstract:The ability of glucocorticoid hormones to interact with glucocorticoid or mineralocorticoid receptors is modulated by 11β‐hydroxysteroid dehydrogenases, interconverting active 11β‐hydroxyglucocorticoids to inactive 11‐ketones. This is, amongst others, important in maintaining a normal salt‐water homeostasis. In this study, we determined the effect of treating rats for 4 days with the potassium sparing diuretic amiloride (5 mg/kg subcutaneously) or with 3 % NaCl in drinking water on renal and hepatic microsomal oxidative and reductive 11 β‐hydroxysteroid dehydrogenase activities and immunoreactive 11 β‐hydroxysteroid dehydrogenase 1 protein. Treatment with amiloride resulted in a 1.5‐fold rise of microsomal corticosterone 11 β‐oxidation rates in kidney (using NAD and NADP as cofactors) and in liver (for NADP only), but had no effect on microsomal 11‐dehydrocorticosterone reduction. Renal 11 β‐hydroxysteroid dehydrogenase 1 immunoreactive protein was increased 1.6‐fold by amiloride. NaCl treatment appeared to have no effect.
Increased Expression of Cholecystokinin‐A Receptor mRNA in Pancreas and Cholecystokinin‐B Receptor mRNA in Oxyntic Mucosa after Porta‐caval Shunting in Rats
Authors: Nylander Anna‐Greta , von Friesen Cristina Paz , Monstein Hans‐Jürg , Yamada Hironori , Chen Duan , Boketoft Åke , Håkanson Rolf
Published: March 2009

Abstract: Porta‐caval shunting enhances the trophic effects of cholecystokinin (CCK)‐A receptor activation on the pancreas and of CCK‐B receptor activation on the ECL cells in the oxyntic mucosa of the rat. The aim of the present study was to study the expression of CCK‐A and CCK‐B receptor mRNA after porta‐caval shunting. Different doses of sulfated CCK‐8 (CCK‐8s) were administered to porta‐caval shunting rats and sham‐operated rats, 4 weeks after the operations. The pancreatic wet weight and DNA content were measured and the ECL cells in the oxyntic mucosa were counted after four days of continuous subcutaneous infusion. Total RNA was isolated from pancreas and oxyntic mucosa for Northern blot analysis of CCK‐A and CCK‐B receptor mRNA. Porta‐caval shunting per se did not affect plasma CCK level nor the weight or DNA content of the pancreas, but resulted in increased number of ECL cells despite the fact that the serum gastrin concentration was reduced. The trophic response of the pancreas to low doses of CCK‐8s was greater in portacaval shunted rats than in sham‐operated rats. Porta‐caval shunted rats displayed an increased CCK‐A receptor mRNA concentration in the pancreas (after stimulation with CCK–8s) and an increased CCK‐B receptor mRNA concentration in the oxyntic mucosa. In conclusion, the porta‐caval shunting‐evoked enhancement of the trophic effect of CCK‐A receptor activation on the pancreas and of CCK‐B receptor activation on the ECL cells is associated with enhanced expression of CCK‐A receptor mRNA in the pancreas and of CCK‐B receptor mRNA in the oxyntic mucosa.
The Potential Role of Iron Chelators in the Treatment of Parkinson's Disease and Related Neurological Disorders
Authors: Gassen Michael , Youdim Moussa B. H.
Published: March 2009

Abstract: Neurodegeneration is characterized by a marked accumulation of iron in the affected brain regions. The reason for this is still unknown. In this article we review the available data on the possible involvement of iron and mediated oxidative stress in the aetiology of Parkinson's disease and related disorders. Iron chelators, if they effectively prevent radical formation, have great therapeutic potential against ischaemia/reperfusion, rheumatoid arthritis, and anthracycline toxicity, which are most likely free radical‐mediated. The efficacy of the best established chelating drug desferal in neurodegenerative disease is limited due to its high cerebro‐ and oculotoxicity. New bioactive chelating agents are currently being developed, among them are oxidative stress activatable iron chelators which are most likely less toxic and can flexibly respond to an increase of free radical formation in the cell.
Comparativein vivoLead Mobilization ofmeso‐ andrac‐2,3‐Dimercaptosuccinic Acids in Albino Wistar Rats
Authors: Jones Mark M. , Singh Pramod K. , Kostial Krista , Blanuša Maja , Piasek Martina , Restek‐Samarožija Nada
Published: March 2009

Abstract:Comparison of theracemicandmesoforms of 2,3‐dimercaptosuccinic acid (DMSA) in lead mobilization from lead‐loaded albino Wistar rats demonstrates that theracemicform is significantly more effective in reducing femur lead levels. After four oral doses at 0.5 mmol/kg, femur lead levels were reduced to 87% of control values bymeso‐DMSA and to 50% of control levels byrac‐DMSA. Similarly, when the dose was increased to 1.0 mmol/kg, femur lead levels were reduced to 69% of control levels bymeso‐DMSA and to 45% of control levels byrac‐DMSA. A similar pattern was found for renal lead levels. Brain lead concentrations were significantly lower in treated groups than in control groups, but no differences were found betweenrac‐ andmeso‐DMSA.Rac‐DMSA is more soluble thanmeso‐DMSA in acetonitrile, ethyl acetate, and ethyl ether. The partition coefficient ofrac‐DMSA in then‐octanol/water system was found to be about 2.8. These results indicate thatrac‐DMSA deserves further attention as a possible substitute formeso‐DMSA.
Possible Involvement of Nitric Oxide Synthase in Oxidative Stress‐Induced Endothelial Cell Injury
Authors: Ishii Masakazu , Yamamoto Toshinori , Shimizu Shunichi , Sano Atsuhiko , Momose Kazutaka , Kuroiwa Yukio
Published: March 2009

Abstract:The purpose of this study was to characterize the protective effect of NG‐nitro‐L‐arginine methyl ester (L‐NAME), an inhibitor of nitric oxide synthase, on oxidative stress‐induced endothelial cell injury. Intracellular oxidative stress was induced by 1‐chloro‐2,4‐dinitrobenzene, a glutathione (GSH) depleting agent, and the leakage of intracellular lactate dehydrogenase was measured as a marker of cell injury. Addition of 1‐chloro‐2,4‐dinitrobenzene (100‐500 μM) induced leakage of lactate dehydrogenase from endothelial cells, and the leakage of lactate dehydrogenase was strongly attenuated by L‐NAME, but not by NG‐methyl‐L‐arginine, also an inhibitor of nitric oxide synthase. However, cell injury induced by the Ca2+ionophore ionomycin was not affected by L‐NAME or NG‐methyl‐L‐arginine. Moreover, neither L‐NAME nor NG‐methyl‐L‐arginine affected GSH depleting agent‐induced or H2O2‐induced cell injury in a rat foetal lung fibroblast cell line which lacks nitric oxide synthase. These results suggest that the protective effect of L‐NAME is likely to be related to nitric oxide synthase, while the inhibition of nitric oxide production may not be involved in the protective effect of L‐NAME, since NG‐methyl‐L‐arginine did not affect endothelial cell injury.
An Affinity‐Modulating Site on Neuronal Monoamine Transport Proteins
Authors: Plenge Per , Mellerup Erling T.
Published: March 2009

Abstract:The dissociation rates of [3H]nisoxetine, [3H]GBR 12935 and [3H]citalopram from, respectively, the rat brain noradrenaline, dopamine and 5‐HT transporters were found to be markedly affected by several drugs. Sertraline strongly attenuated the rate of dissociation of [3H]nisoxetine from the noradrenaline transporter, while citalopram strongly attenuated that of [3H]citalopram from the 5‐HT transporter. The effects of both drugs were stereospecific. Less potent affinity‐modulating drugs were identified with regards to [3H]GBR 12935 dissociation from the dopamine transporter. All three neuronal monoamine transporters may thus have specific affinity‐modulating sites which change the function of the transporters with possible implications for the reuptake of monoamines released during synaptic activity.
Oral Vanadyl Sulphate Does not Affect Blood Cells, Viscosity or Biochemistry in Humans
Authors: Fawcett J. P. , Farquhar S. J. , Thou T. , Shand B. I.
Published: March 2009

Abstract: Vanadyl sulphate (VOSO4) is used to improve performance in weight training athletes. Concerns about its safety have arisen because vanadium compounds may cause anaemia and changes in the leukocyte system. In this study, the effects of oral VOSO4 (0.5 mg/kg/day) on haematological indices (red and white cell and platelet counts, red cell mean cell volume and haemoglobin level), blood viscosity (haematocrit, plasma viscosity and blood viscosity at 10s−1 and 100s−1 shear rates) and biochemistry (lipids and indices of liver and kidney function) were investigated in a twelve week, double blind, placebo controlled trial in 31 weight training athletes. Blood viscosity was evaluated at 0, 2, 4, 8 and 12 weeks and haematological indices and biochemistry were measured before and at the end of treatment. Both the treatment group and placebo group showed increases in haematocrit (3.3‐3.6%) and blood viscosity (9‐11% at 100s−1 shear; 35‐38% at 10s−1 shear) but there were no significant effects of treatment. Similarly there were no treatment effects on haematological indices and biochemistry. Concerns about the adverse effects of oral vanadyl sulphate on blood are not supported by the results of this trial.
An Appraisal of the Pharmacological and Toxicological Effects of a Single Oral Administration of 3,4‐Methylenedioxymethamphetamine (MDMA) in the Rat
Authors: Souza I. De , Kelly J. P. , Harkin A. J. , Leonard B. E.
Published: March 2009

Abstract:This study examined some acute pharmacological and toxicological effects of 3,4 methylenedioxymethamphetamine (MDMA, “Ecstasy”) over a range of doses (20, 40, 80, 160 and 320 mg/kg orally) in adult female rats. Deaths were observed from the 40 mg/kg MDMA group onwards. Reductions in body weight change, food and water intake were found in the 80 mg/kg group, whilst food intake alone was reduced in the 20 and 40 mg/kg groups. Significant hyperthermic responses were found over the first 8 hr following MDMA administration which were dose‐related. A significant hyperactivity of approximately 9 hr duration was observed in the 20 mg/kg and 40 mg/kg groups, whereas there was evidence of a serotonin syndrome in the higher dosage groups. Thus, acute oral administration of MDMA results in a variety of measurable responses. The cause of death in this study is probably a combination of serotonin syndrome and hyperthermia.
How Does Cystitis Affect a Comparative Risk Profile of Tiaprofenic Acid with Other Non‐Steroidal Antiinflammatory Drugs? An International Study Based on Spontaneous Reports and Drug Usage Data
Authors:   The ADR Signals Analysis Project (ASAP) Team:, Lindquist Marie , Pettersson Monica , Edwards Ivor Ralph , Sanderson Joel H. , Taylor Norman F. A. , Fletcher A. Peter , Schou Jens S. , Savage Ruth
Published: March 2009

Abstract: Series of well‐documented case reports strongly suggest a causal association between tiaprofenic acid and a form of aseptic cystitis, which can cause serious and long‐term morbidity if the drug is not withdrawn promptly. These findings are supported in the Australian and UK spontaneous reporting data‐bases. Using sales data as the denominator, a comparison of NSAIDs in the WHO drug monitoring data‐base indicates that the reaction is specific to tiaprofenic acid and cannot be accounted for by changes in reporting patterns in certain countries or years. Delayed recognition is an important feature of this reaction and possible reasons for this are discussed. Comparison of the risk profiles of seven NSAIDs indicated that tiaprofenic acid had the poorest risk profile, compared with NSAIDs of similar efficacy, when cystitis reports were included. The results suggest that combining spontaneous reports, classified according to severity, with sales data may enhance the ability of drug monitoring data‐bases to contribute to risk benefit appraisals.
Pharmacokinetics, Toxicity, Side Effects, Receptor Affinities andin vitroRadiosensitizing Effects of the Novel Metoclopramide Formulations, Sensamide and Neu‐Sensamide
Authors: Pero Ronald W. , Olsson Anders , Simanaitis Mecislovas , Amiri Amir , Andersen Inger
Published: March 2009

Abstract:Metoclopramide is a drug which has experienced worldwide use in the clinic for over 30 years as an antiemetic. Recently, it has also been shown to possess radio‐and chemosensitizing properties in both animal tumour models and humans at the higher dose of 2 mg/kg. Two new metoclopramide formulations are being clinically developed and they differ mainly in whether the pH of their formulations are acidic (pH 2.5‐3.5) or neutral (pH 6.5‐7.0). Here we report that intramuscular administration of neutral metoclopramide is about 100% bioavailable, safer and with reduced side effects compared to acidic metoclopramide delivered by intramuscular injection to rats within the dose range of 3.5 to 14 mg/kg. The intramuscular administration of metoclopramide was also about 100% bioavailable compared to the intravenous route of administration. Furthermore, neutral metoclopramide had significantly decreased affinity for dopamine D2receptors and increased affinity for 5‐hydroxytryptamine3receptors, but the radiosensitizing potency was the same, when compared to equimolar concentrations of acidic metoclopramide. Taken together these data support the continued development of neutral metoclopramide for high dose intramuscular administration of metoclopramide for future clinical use as both an antiemetic and radiosensitizer.
The in vivo Effects of Interleukin‐3 on Histamine Levels in Non‐Hodgkin's Lymphoma Patients
Authors: Hovgaard Doris J. , Skov Per Stahl , Nissen Nis I.
Published: March 2009

Abstract: Recombinant human Interleukin‐3 (RhIL‐3) is a haemopoietic growth factor with effect both on early and differentiated cells, such as eosinophils and basophils, and it also acts as a histamine‐releasing agent. The purpose of the present study was to examine whether in vivo rhIL‐3 administration after chemotherapy affected basophil histamine levels and whether a concordance between rhIL‐3 induced histamine release and side effects during the treatment could be demonstrated. Thirty patients with non‐Hodgkin's lymphoma entered the study. All patients received 6 courses of chemotherapy, rhIL‐3 was administered subcutaneously once daily after the second and the fourth course of chemotherapy from cycle day 2–15 at the dose levels 0.5, 1.0, 5.0, 7.5 and 10 μg/kg with 6 patients at each dose level. In cycle 6 recombinant human Granulocyte‐Macrophage Colony‐Stimulating Factor (rhGM‐CSF) (3.0 μg/kg) was administered sequential/concurrent day 9–15 to rhIL‐3 (day 2–15) at all dose levels except 7.5 μg/kg, where rhIL‐3 was given day 2–8 and rhGM‐CSF sequential day 9–15. Cycles 1, 3 and 5 served as control cycles with no cytokine therapy. During rhIL‐3 treatment, and after CHOP chemotherapy, the basophil counts increased moderately especially during the recovery period day 15–22, and mainly at the two highest dose levels 7.5 and 10 μg/kg, but never exceded the normal upper limit. Histamine levels in basophils were the same in patients before chemotherapy and healthy volunteers, and except from a trend to increased histamine level at 10 μ/kg on day 15, no difference was noted between rhIL‐3 cycles and control cycles. Within 3–4 hr after rhIL‐3 administration, a drop in histamine level in basophils was noted, which could be due to histamine‐releasing properties of rhIL‐3 as previously demonstrated by in vitro studies. No serious side effects were noted during the cytokine treatment, and despite that most patients had mild flushing of the face, neck and upper chest, no patients experienced sensitization throughout the study. Although a significant increase in rhIL‐3‐induced histamine release from basophils was noted in some of the patients, no correlation to the dose of rhL‐3 was found, and no correlation was noted between side effects and histamine release or histamine levels in basophils.
How clean is a mini‐pig? ‐ Impressions and suggestions of a pathologist working in the field of toxicology
Authors: Rinke Matthias
Published: March 2009

Abstract: Gross and histopathological investigations of more than 100 minipigs revealed: 1. Findings due to repeated blood sampling. For anatomical reasons the thyroid gland of pigs can be injured during blood sampling. Histopathological investigation of thyroid glands often revealed inflammatory and reparative fibrotic changes of this organ. Depending on the grade of damage, thyroid hormone levels may vary. To avoid misinterpretation of results, most careful blood sampling by experienced personnel is recommended. 2. Findings due to viral, bacterial and parasitic infections. These concerned mainly the lungs which often showed pneumonic alterations. In case of parasitic invasion, die skeletal muscles may reveal degenerative changes due to sarcosporidia (re‐) infection. Therefore, optimal hygienic conditions, e.g. during blood sampling, and continuing health monitoring are recommended. 3. Findings due to preventive iron administration. Months after preventive iron‐dextran administration at the breeding station, histopathological examination revealed siderin accumulation in a number of organs, namely in the cells of the mononuclear phagocytic system in liver and kidneys. As a unique finding an intraglomerular siderin deposition in the mesangial cells with subsequent glomerulosclerosis in certain glomeruli was observed.
Venous Catheter Implantation in the Minipig Surgical Approaches and Refinements
Authors: Webb Anthony J.
Published: March 2009

Abstract: In spite of requiring invasive implantation procedures, chronic venous catheters offer a number of benefits in biomedical research involving pig:

– avoidance of long term or repeated stress due to restraint for venepuncture

– assured delivery of compounds into venous blood

– sampling is always from the same site

– use of large central veins ensures representative samples, in large quantities

– central venous sites allow rapid dilution or bufferng of compounds whcich may potentially irritant

– facilitate long term and infusion studies

Common sites of access to the venous system are jugular vein or its tributaries and the femoral vein. Experience has shown the jugular approach to the cranial vena cava to give superior performance. The presentation will focus on this approach by surgical exposure of the vessel with reference to the potential use of percutaneous introducer sheaths and Seldinger technique which offer reduced invasiveness of catheter insertion.

Catheters may be either exteriorised through the skin or attached to a totally implanted vascular access port (VAP). The management of the skin‐implant interface with materials such a Dacron velour which favour adherence to the animal's own tissue, obliterating space in which infection may arise and providing anchorage is advocated. Fully implantable pumps for infusion studies may also be used.

Catheter related sepsis (CRS) is the chief and most significant complication of chronic vascular access in any species, in the pig, CRS is particularly resistant to therapy in comparison with other species. Methods for prevention of catheter related will be outlined.
The Use of Minipigs in Dermal Toxicity Testing
Authors: Vogel B. , Singer T.
Published: March 2009

Abstract: Pigs have been extensively used for surgical and physiological research for years, due to their similarities to humans. For human medical research, wether the blood and lymph, or circulation, respiration, exctetion and urine, digestion, metabolism, nutrition, endocrine and nervous system, and especially the cutaneous system, it appears that the pig is the ideal experimetal animal. While rabits are commonly used for the assessment of primary dermal irritation, pigs or minipigs have been considered to be a good model for dermal permeability and toxicity studies. The skin of pigs fulfills the requirements of a model for human skin. Human and porcine skin are similar with regard to sparsity of the pelage, thickness and general morphology, epidermal cell turnover time and size, orientation and distribution of vessels in the skin. The particular thin haircoat and the lack of pigment of the minipig makes it ideal for dermal studies. The size of the animal also provides the additional practical advantage of abundant surface area for multiple‐site and long‐term testing. Non‐invasive skin examination methods of human dermatology, for example reflectometric skin color measurement or high‐resolution ultrasonography, can be used as monitoring tools in dermal toxicity studies with minipigs. Skin alterations can be easily quantified by these methods. Despite there are some limitations, all in all there is no animal species that mimics the human skin better than the pig.
Aspirin for the Second Hundred Years: New Uses for an Old Drug
Authors: Vainio Harri , Morgan Gareth
Published: March 2009

Abstract: The history of aspirin can be traced back to ancient Egypt where extract of willow bark was used to treat inflammation. The active component of the extract was identified as the glucoside of salicylic alcohol. The severe gastric side effects associated with the use of sodium salicylate prompted the synthesis of the o‐acetyl‐derivative as a possible pro‐drug. In fact, acetylsalicylic acid was antiinflammatory, analgesic and antipyretic but also ulcerogenic to the stomach. Acetylsalicylic acid was synthesized one hundred years ago, and was mass‐produced under the commercial name of ‘Aspirin’(Dreser, 1899) by the German company Bayer for the treatment of fever and rheumatism.
Lead Binding to δ‐Aminolevulinic Acid Dehydratase (ALAD) in Human Erythrocytes
Authors: Bergdahl Ingvar A. , Grubb Anders , Schütz Andrejs , Desnick Robert J. , Wetmur James G. , Sassa Shigeru , Skerfving Staffan
Published: March 2009

Abstract: Over 99% of the lead present in blood is usually found in erythrocytes. To investigate the nature of this selective accumulation of lead in erythrocytes. the specific binding of lead to proteins in human erythrocytes was studied using liquid chromatography coupled to inductively coupled plasma mass spectrometry (LC‐ICP‐MS). The principal lead‐binding protein had a mass of approximately 240 kDa, and adsorption to specific antibodies showed that the protein was δ‐aminolevulinic acid dehydratase (ALAD). Thus, the previous notion that lead in erythrocytes was bound primarily to haemoglobin has to be revised. Furthermore, in lead‐exposed workers, the percentage of lead bound to ALAD was influenced by a common polymorphism in the ALAD gene. Specifically, in seven carriers of the ALAD2 allele, 84% of the protein‐bound lead recovered was bound to ALAD compared to 81% in seven homozygotes for the ALAD1 allele whose erythrocytes were matched for blood‐lead concentration. The small difference was statistically significant in Wilcoxon matched‐pairs signed‐rank test (P=0.03). No ALAD allele‐specific difference in ALAD‐bound lead was found among 20 unexposed controls. Perhaps the difference in ALAD‐bound lead can provide an explanation for the previously reported finding of higher blood‐lead levels among carriers of the ALAD2 allele than among ALAD1 homozygotes in lead‐exposed populations.
Glutathione Pretreatment Lessens the Acute Liver Injury Induced by Carbon Tetrachloride
Authors: Arosio Beatrice , Santambrogio Daniela , Gagliano Nicoletta , Ryan Anthony , Biasi Fiorella , Vergani Carlo , Annoni Giorgio
Published: March 2009

Abstract:We explored the protective activity of glutathione (GSH) in a rat model of carbon tetrachloride‐induced acute liver damage. Histological examination of livers from GSH‐pretreated rats revealed minor damage, confirmed by biochemical parameters of liver cell necrosis evaluated both 24 and 48 hr after hepatotoxin delivery. In addition we quantified changes in hepatic steady‐state levels of albumin, type I procollagen, transforming growth factor‐β1 and tumour necrosis factor‐α mRNAs. Even at the molecular level and above all for the albumin gene, it appears that GSH lessens the effect of the hepatotoxin, however the protection of the thiol is restricted to the first 24 hrs and is almost totally exhausted after 48 hr. Since, only 24 hr after CC14 delivery, GSH abundance determined in erythrocytes and liver is almost equal in the controls and in the GSH injected rats, but significantly higher than in the only intoxicated animals (P<0.05, intraerythrocyte content), we conclude that the thiol pretreatment exerts an effective but transient protection.
Arterial Function in Mineralocorticoid‐NaCl Hypertension: Influence of Angiotensin‐Converting Enzyme Inhibition
Authors: Mäkynen Heikki , Kähönen Mika , Wu Xiumin , Hutri‐Kähönen Nina , Tolvanen Jari‐Petteri , Pörsti Ilkka
Published: March 2009

Abstract:Angiotensin‐converting enzyme inhibitors have been suggested to improve the function of arterial endothelium and smooth muscle not only through inhibition of angiotensin II formation and reduction of blood pressure, but also via additional pathways, e.g. potentiation of endogenous kinins and enhancement of endothelial autacoid formation. Therefore, we investigated whether 10‐week‐long quinapril therapy (10 mg kg−1day−1) could beneficially influence the function of mesenteric arterial ringsin vitroin deoxycorlicosterone‐NaCl‐treated Wistar‐Kyoto rats, a model of hypertension which is known to be resistant to angiotensin‐converting enzyme inhibition. The quinapril treatment had no long‐term blood pressure‐lowering effect nor did it reduce the associated cardiac hypertrophy in deoxycorticosterone‐NaCl hypertension. In noradrenaline‐precontracted arterial rings the endothelium‐dependent relaxations to acetylcholine and adenosine 5′‐diphosphate as well as the endothelium‐independent relaxations to nitroprusside and isoprenaline were clearly attenuated in the deoxycorticosterone‐NaCl‐treated rats. However, the quinapril therapy was without significant effect on any of these dilatory responses. In the presence of the nitric oxide synthase inhibitor NG‐nitro‐L‐arginine methyl ester, the relaxations to acetylcholine in untreated and quinapril‐treated hypertensive animals were practically absent, whereas in normotensive rats distinct relaxations to higher concentrations of acetylcholine were still present. Interestingly, when endothelium‐dependent hyperpolarization was prevented by precontracting the preparations with potassium chloride, no differences were found in relaxations to acetylcholine and adenosine 5′‐diphosphate between the study groups. Exogenous bradykinin induced small comparable contractions in endothelium‐intact mesenteric arterial rings from all study groups. In conclusion, the 10‐week‐long quinapril therapy did not have any significant effects on arterial function in deoxycorticosterone‐NaCl hypertensive rats. Therefore, the present results stress the roles of reduced blood pressure and diminished angiotensin II formation in the beneficial vascular effects of long‐term angiotensin‐converting enzyme inhibition in the present model of hypertension. Furthermore, since the relaxations to acetylcholine and adenosine 5′‐diphosphate in the deoxycorticosterone‐NaCl‐treated rats were attenuated in the absence and presence of nitric oxide synthase inhibition but not under conditions which prevented hyperpolarization, impaired endothelium‐dependent relaxation to agonists can be attributed to diminished endothelium‐dependent hyperpolarization in this model of hypertension.
Arterial Responses to Bradykinin after Ramipril Therapy in Experimental Hypertension
Authors: Hutri‐Kähönen Nina , Pörsti Ilkka , Wu Xiumin , Tolvanen Jari‐Petteri , Sallinen Kirsimarja , Kähönen Mika
Published: March 2009

Abstract:Angiotensin‐converting enzyme inhibitors have been shown to potentiate relaxations to kinins in several arteries, but the effects of long‐term therapy on the responses to bradykinin in normotensive and hypertensive animals remain largely unknown. Therefore, the effects of 12‐week‐long ramipril therapy (1 mg kg−1day−1) on responses of mesenteric arterial ringsin vitrowere studied in spontaneously hypertensive rats and normotensive Wistar‐Kyoto rats. Endothelium‐dependent relaxations of noradrenaline‐precontracted rings to acetylcholine were similar in normotensive rats and ramipril‐treated hypertensive rats and more pronounced than in untreated hypertensive group. Higher concentrations of bradykinin (0.1‐1 μM) induced slight contractions in noradrenaline‐precontracted endothelium‐intact rings of normotensive groups and untreated hypertensive group, whereas no response or a transient relaxation were observed in ramipril‐treated hypertensive rats. Interestingly, in ramipril‐treated hypertensive rats but not in the other groups, 20‐min. pretreatment of arterial rings with ramiprilat unmasked or potentiated the relaxations to bradykinin, and these bradykinin‐induced relaxations were effectively inhibited by the B2‐kinin receptor antagonist Hoe‐140. In conclusion, ramipril treatment clearly improved endothelium‐dependent arterial relaxation to acetylcholine, and potentiated of even unmasked the dilatory response mediated via the endothelial B2‐kinin receptor in spontaneously hypertensive rats. Since these enhancing effects on arterial relaxationin vitrocould not be attributed to reduced breakdown of bradykinin, the present results suggest that long‐term angiotensin‐converting enzyme inhibition potentiated the actions of kinins at level of B2‐kinin receptors.
Endotoxin Increases Oxidative Injury to Proteins in Guinea Pig Liver: Protection by Dietary Vitamin C
Authors: Cadenas Susana , Rojas Caridad , Barja Gustavo
Published: March 2009

Abstract: Current information suggests that oxidative damage plays a key role in septic shock induced by endotoxin. This raises the possibility that dietary antioxidant vitamins could protect against endotoxin damage. In this study, the effects of endotoxin administration on protein and lipid oxidative damage and endogenous antioxidants were studied in the liver of guinea pigs previously supplemented with marginal or optimum levels of dietary vitamin C, vitamin E or both. Vitamins C and E inhibited in vitro lipid peroxidation in endotoxin‐treated animals. Endotoxin significantly increased oxidative damage to liver proteins in animals receiving low doses of both vitamins, a result described here for the first time. This increase was totally prevented in guinea pigs supplemented with vitamin C alone or in combination with vitamin E, a treatment which strongly increased liver ascorbate. Vitamin C caused small significant increases in superoxide dismutase and glutathione, increased uric acid, and synergically increased α‐tocopherol levels in vitamin E‐supplemented animals treated with endotoxin. The results show that dietary vitamin C protects against endotoxin‐induced oxidative damage to proteins in the guinea pig liver. This seems mainly due to a direct protective effect of the increased hepatic ascorbate levels present in vitamin C‐supplemented animals.
Systemic and Ocular Absorption and Antagonist Activity of Topically Applied Cyclopentolate in Man
Authors: Haaga Marko , Kaila T. , Salminen L. , Ylitalo Pauli
Published: March 2009

Abstract: Ocular and systemic absorption and antagonist activity of topical 1 % cyclopentolate were studied in 11 elderly patients undergoing extracapsular cataract extraction, and in 8 healthy female volunteers. The patients recieved two 35 μl drops of cyclopentolate unilaterally and the healthy volunteers one 30 μl drop bilaterally to the lower conjunctival cul‐desac of the eye. The drug concentrations were measured with radioreceptor assay and receptor occupancies with radiooceupancy assay using isolated rat brain muscarinic cholinoceptors. In the patient group, cyclopentolate concentrations in aqueous humour were approximately 3000 times higher than those in plasma. Muscarinic cholinoceptors were occupied totally (more than 99.9%) by aqueous humour and 3‐18% by plasma taken at 55‐125 min. after the drug application. In healthy volunteers peak plasma concentration of cyclopentolate, 2.06 ± 0.86 (mean ± S.D.) nM, occurred at 53 min., maximum receptor occypancy being 5.9 ± 2.1%. The maximum pupillary dilatation occured at 30 min. after the drug application. At the same time the near point of vision was extended to more than 50 cm in all subjects. After topical application plasma receptor occupancy was not high enough to cause any significant changes in heart rate and in PQ time. None of the subjects experienced subjectively or objectively adverse effects to be attributed to cyclopentolate.
A Fish Oil‐Derived Concentrate Enriched in Eicosapentaenoic and Docosahexaenoic Acid as Ethyl Esters Inhibits the Formation and Growth of Aberrant Crypt Foci in Rat Colon
Authors: Paulsen Jan Erik , Stamm Tone , Alexander Jan
Published: March 2009

Abstract: It was examined whether the fish oil derived n‐3 fatty acid concentrate K85 (51.0% of eicosapentaenoic acid, 35.3% of docosahexaenoic acid and 7.7% of other n‐3 fatty acids, all as ethyl esters) could inhibit the initial formation of aberrant crypt foci and the later growth of pre‐existing aberrant crypt foci in the colon of male F344 rats treated with the carcinogens dimethylhydrazinc or azoxymethane, the proximate metabolite of dimethylhydrazine. Given intragastrically 5 times a week, K85 caused a dose‐dependent reduction of the initial (week 0‐6) formation of aberrant crypt foci induced by azoxymethane (2 × 15 mg/kg body weight/injection the first two weeks). The number of aberrant crypt foci was reduced by 36% (P < 0.001) with 3.0 g K85/kg body weight/dose, the largest dose tested. The reduction was most pronounced (46%, P = 0.009) among the fastest growing aberrant crypt foci (foci with 3 or more aberrant crypts). When given in a later phase of the carcinogenesis (week 17‐23) a similar intragastric treatment with K85 caused a dose‐dependent reduction of the growth of pre‐existing aberrant crypt foci induced by dimethylhydrazine (3 × 20 mg/kg body weight/injection the first week). The crypt multiplicity (aberrant crypt/focus) was reduced by 22% (P = 0.016) with 2.24 g K85/kg body weight/dose, the largest dose tested. This was sufficient to completely block the growth of the pre‐existing aberrant crypt foci in the treatment period. The arrest of crypt multiplication was further documented by the 63% reduction (P = 0.03) of the large aberrant crypt foci (foci with 9 or more aberrant crypts). The total number of aberrant crypt foci was not affected.
Tissue Distribution of Sex Steroids: Concentration of 17β‐Oestradiol and Cyproterone Acetate in Selected Organs of Female Wistar Rats
Authors: Schleicher Frauke , Tauber Ulrich , Louton Tom , Schunack Walter
Published: March 2009

Abstract:The tissue distribution of 17β‐oeslradiol and cyproterone acetate was investigated after intravenous and intragastric administration to female Wistar rats by measuring the time course of the concentration of the sex steroids in plasma, liver, kidney, brain, and heart by radioimmunoassay. Test substances were administered intravenously in doses of 0.1 mg/kg each and intragastrically in doses of 10 mg/kg (17β‐oestradiol) and 0.1 mg/kg (cyproterone acetate) corresponding to the expected oral bioavailability. Tissue distribution was assessed within each mode of administration by AUCorgan/ AUCplasma‐quotients (Q‐values), and between both routes of administration by F‐values representing (bio‐ and organ availability) and R‐values, which express the organ load after intragastric compared to intravenous administration if the same amount of drug has been made bioavailable in the plasma after both routes (for explanation see next page). The absolute bioavailability of 17β‐oestradiol after intragastric administration of 10 mg/kg was ca. 8%. The oestradiol liver load after intragastric administration was about 20 times higher than after intravenous administration, whereas the drug load of other organs was independent of the administration route. Cyproterone acetate was completely bioavailable after intragastric administration in a dose of 0.1 mg/kg. Cyproterone acetate levels and AUC‐values in all organs investigated were higher when compared to the plasma with highest levels in the liver. The organ distribution of cyproterone acetate including the drug liver load was independent of the route of administration.
(‐)Deprenyl (Selegiline), a Catecholaminergic Activity Enhancer (CAE) Substance Acting in the Brain
Authors: Knull Joseph
Published: March 2009

Abstract: β‐Phenylethylamine and its long acting derivatives, the amphetamines, are mixed‐acting stimulants of the sympathetic system in the brain. They enhance the impulse propagation mediated release of catecholamines (catecholaminergic activity enhancer effect) and displace catecholamines from their stores (catecholamine releasing effect). (‐)Deprenyl (selegiline), a close structural relative to (‐)methamphetamine. is the first catecholaminergic activity enhancer substance in clinical use devoid of catecholamine releasing property, being therefore free of the ‘cheese effect’ and of the dependence capacity of the amphetamines. (‐)Deprenyl is also a highly potent and selective, irreversible inhibitor of monoamine oxidase type B. (‐)Deprenyl enhances superoxide dismutase and catalase activity in the striatum, protects the nigrostriatal dopaminergic neurons against selective neurotoxins (6‐hydroxy‐dopamine. MPTP, 4 N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine) and prevents characteristic age‐related morphological changes in the neurocytes of the substantia nigra. Maintenance of rats on (‐)deprenyl during the postdevelopmental phase of their life slows the age‐related decline of sexual and learning performances and prolongs life significantly. Patients with early, untreated Parkinson's disease maintained on (‐)deprcnyl need levodopa significantly later than their placebo‐treated peers, and when on levodopa plus (‐)deprenyl, they live significantly longer than patients on levodopa alone. In patients with moderately severe impairment from Alzheimer's disease, treatment with (‐)deprenyl slows the progression of the disease. It may be supposed that a prophylactic low dose administration of a safe catecholaminergic activity enhancer substance during the postdevelopmental phase of life will slow the age‐related decline of behavioral performances, delay natural death and decrease susceptibility to Parkinson's disease and Alzheimer's disease.
Effect of Cigarette Smoke on UDP‐Glucuronosyltransferase Activity and Cytochrome P450 Content in Liver, Lung and Kidney Microsomes in Mice
Authors: Villard Pierre‐Henri , Hcrber Régine , Sérée Erie Marie , Attolini Laurence , Magdalou Jacques , Lacarelle Bruno
Published: March 2009

Abstract:The effect of cigarette smoke on the expression of several cytochromes P450 (CYP) and UDP‐glucuronosyltransferases (UGT) was studied in mice. The animals were exposed to cigarette smoke for 4 to 30 days. Enzymatic activities supported by CYP1A1, 1A2, 2B, 2E1 and the glucuronidation activity toward phenols were measured in lung, liver and kidney microsomes. Cigarette smoke induced several CYPs, especially in lung. CYP2E1 was more induced than CYP1A1 in this organ. The expression of CYP2E1 was also increased in kidney (5.6 times after 30 days). The glucuronidation in kidney was non‐sensitive to the treatment whatever substrate used. In contrast, this activity was enhanced in liver and particularly in lung, in which the glucuronidation of 1‐naphthol and 2‐hydroxybiphenyl was increased by 122 and 180%, respectively. Interestingly, the times of induction differed according to the substrate used, thus suggesting the presence of different UGTs active toward phenols that were differentially affected by cigarette smoke. The LIGT activities toward phenols were low in lung, when compared with those measured in liver or kidney. In conclusion, cigarette smoke greatly affected both glucuronidation activity and the hydroxylation reactions supported by CYPs in mouse liver and lung.
Efficacy of Glutamate Receptor Antagonists in the Management of Functional Disorders in Cytotoxic Brain Oedema Induced by Hexachlorophene
Authors: Häntzschel Annegret , Andreas Klaus
Published: March 2009

Abstract:The hexachlorophene‐induced cytotoxic brain oedema is an experimental model of brain damage, suitable for testing cerebroprotective substances (Andreas 1993). In order to examine whether glutamate receptors are involved in mediating functional disorders due to neurotoxic brain damage, we have studied the protective effects of several competitive and non‐competitive antagonists using adult male Wistar rats in a simple “ladder‐test” for assessing coordinative motor behaviour. Hexachlorophene‐induced brain damage was verified by histological examination of the cerebellum with vacuolation of white matter, astrocyte hypertrophy and astrocyte proliferation taken as signs of neurotoxic injury. The non‐competitive N‐methyl‐D‐aspartate (NMDA) antagonist dizocilpine maleate (MK‐801) decreased the motor disturbance on the first and second day of the “ladder‐test” when applied in the doses 0.1 mg/kg and 0.2 mg/kg intraperitoneally for 3 weeks during the hexachlorophene treatment. Acute MK‐801 administration (0.1 mg/kg intraperitoneally) after 3 weeks hexachlorophene exposure improved the coordinative motor response only on the first day. When testing the competitive NMDA receptor antagonist 2‐amino‐5‐phosphonopentanoic acid (AP‐5) in the dose 1.0 mg/kg intraperitoneally the motor disturbance was lowered significantly earlier than in spontaneous remission. Similar effects were observed with 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX) in the dose of 0.8 mg/kg intraperitoneally, an antagonist interacting both with the strychnine‐insensitive binding site for glycine within the NMDA receptor complex and with the kainate/(±)‐α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) receptor complex. Concurrent MK‐801 administration decreased the vacuolation of white matter. The results suggest that NMDA receptors and non‐NMDA receptors are involved in development of functional disorders induced by hexachlorophene.
Effects of Thiopental on Contractile and Electrophysiological Properties of Single Canine Left Ventricular Cells
Authors: Kubo Hideyuki , Hatakcyama Noboru , Sutone Toshihiko , Shibuya Nobuko , Lto Yusuke , Yamamura Shigeo , Momose Yasunori
Published: March 2009

Abstract:The effects of thiopental on contraction, membrane potential and membrane ionic currents were studied in single canine left ventricular cells. Thiopental 10−5and 10−4mol/1 reduced the cell‐shortening from 7.02 ± 0.64 μm to 5.66 ± 1.39 and 3.48 ± 0.64 μm respectively (mean±S. D, N = 10, 0.5 Hz). This effect was enhanced in higher (>1.0 Hz) electrical stimulation frequencies. Also, thiopental decreased the plateau phase and shortcned the duration of action potential. On the other hand, voltage clamp experiment revealed that thiopental 10−6, 10−5, and 10−4mol/1 reduced peak Ca2+current from 520±48 pA to 387 ± 60 pA, 261 ± 84 pA, and 84 ± 36 pA respectively (mean + S. D., N = 8), and showed a use‐dependent block of Ca2+current. However, only a high dose of thiopental (10−4mol/1) inhibited the Na4current. We conclude that the negative inotropic effect of thiopental on the heart is mediated mainly via inhibition of the Ca2+current.
Peroxynitrite: A Putative Cytotoxin
Authors: Demiryürek A. Tuncay , Çakici Iclal , Kanzik Ilker
Published: March 2009

Abstract:In recent years it has become apparent that peroxynitrite. which is one of the toxic metabolites originating from the reaction of nitric oxide and superoxide presents a number of pathologic states in which free radicals are thought to be involved. Peroxynitrite is capable of oxidizing a wide variety of biomolecules including plasma, proteins, lipids, carbohydrates and nucleic acids. Peroxynitrite is involved in the hydroxylation of aromatic compounds and acts as a nitrating agent. It modifies free or protein‐associated tyrosine residues to give nitrotyrosines, leaving a marker detectablein vivo.Peroxynitrite has been implicated in the pathophysiology of a variety of diseases including inflammation, atherosclerosis, arthritis, endotoxemia, ischaemia‐reperfusion injury, or acute respiratory distress syndrome. Development of specific peroxynitrite scavengers may provide new approaches for the effective treatment of these disease states.