bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Protein Chemical Hydrophobization on Antiglucose Oxidase Immunoglobulin Production in Mouse
Authors: Shi Qin , Domurado Martine , Domurado Dominique
Published: March 2009

Abstract: One problem resulting from the therapeutic use of enzymes is the adverse immunological reactions. In order to study the immunoglobulin production elicited into mice by different derivatives of an enzyme, glucose oxidase was chosen as a model. The immunoglobulin productions induced by apoglucose oxidase, prepared by removing flavine adenine dinucleotide from the native enzyme through an acidic treatment and devoid of enzymatic activity, by metaperiodate‐oxidized glucose oxidase that lost about 50% of its carbohydrate moiety, and by propyl aliphatic chains‐coupled glucose oxidase were as intense as that induced by native glucose oxidase. On the other hand, coupling hexyl aliphatic chains to the enzyme did change its ability to stimulate antibody production. This hydrophobized preparation induced a low titer of antibody after repeated intravenous or subcutaneous injections. This result suggests a simple strategy for reducing the immunogenicity of foreign proteins and for decreasing the risk of immunological complications in enzyme therapy.
Characterization of a P2Y Purinoceptor in the Brain
Authors: Simon Joseph , Webb Tania E. , Barnard Eric A.
Published: March 2009

Abstract: Little has been known of the abundance in the brain of any of the G protein coupled P2 purinoceptors nor their pharmacology. Here we show that [35S]dATPαS is a suitable radioligand for investigating these receptors and hence that they are exceptionally abundant both in one‐day‐old chick (Bmax: 37 pmol agonist sites/mg protein) and adult rat brain membranes (Bmax: 39 pmol/mg protein). [35S]dATPαS (which is selective for P2Y over the P2X types of purinoceptor) binds with high affinity to these sites in the chick (Kd: 13.3 nM) and in the rat brain membranes (Kd; 9.1 nM). The rank order of potency of purinoceptor‐active agonists and antagonists displacing [35S]dATPαS binding is: dATPαS>(3′‐deoxyATP, 2‐methylthioATP ATPαS, ATP) >2′‐deoxyATP>2‐methylthioADP>ADP>> suramin, Reactive Blue‐2>>UTR L‐β, γ‐methyleneATP, adenosine; this defines these binding sites as P2Y subtypes of the P2 purinoceptors. This pharmacological profile of purinergic ligands is in excellent agreement with the potency order established for the recombinant P2Y1 purinoceptor from chick brain, identifying the great majority of the brain P2 purinoceptors as identical or very similar to the native P2Y1 receptor.
Does the Dopamine Receptor Subtype Selectivity of Antipsychotic Agents Provide Useful Leads for the Development of Novel Therapeutic Agents?
Authors: Hacksell Uli , Jackson David M. , Mohell Nina
Published: March 2009

Abstract:Antipsychotic agents share the ability to antagonize dopamine (DA) receptors, and correlation studies have indicated that the clinical efficacy of neuroleptic agents may be coupled to their affinity for D2receptors. More recently, a family of DA D2‐like receptors has been identified. These receptors include the D2A, D2B, D3and D4receptors. On the basis ofin vitroreceptor‐binding studies, it has been suggested that the atypical profile of clozapine might be related to a selective effect on the D4receptor subtype. We have studied the receptor‐binding profiles of a series of antipsychotic agents and evaluated some of the compounds in behavioural assays in the rat. Most of the antipsychotic agents lack selectivity for DA‐receptors as well as selectivity for the various DA‐receptor subtypes. Because of this lack of selectivity, it is impossible to draw firm conclusions about the role of any particular receptor in the clinical profile of the neuroleptic agents. Furthermore, the pharmacology of potential human metabolites has to be taken into account in a proper analysis of the clinical profile. Consequently, most speculations on the key‐target of clinically interesting antipsychotics (including clozapine) may be of little practical value. Clinical studies with receptor (subtype)‐selective agents will be more informative.
Cell Systems for Use in Studies on the Relationship Between Foreign Compound Metabolism and Toxicity
Authors: Oesch Franz , Diener B.
Published: March 2009

Abstract:Since the metabolism of most foreign compounds is predominantly controlled by hepatic in metabolism, isolated hepatocytes in most cases quite well predict the pattern of the overall metabolism of a given compound. Methods have been developed for cryopreserving isolated hepatocytes from man and other species with satisfactory maintenance of foreign compound metabolizing enzyme activities. The installation of a bank of cryopreserved hepatocytes from different species is possible and may be used for rational species extrapolation. It is necessary for some toxicological investigations to have hepatocytes which retain their differentiated status in culture for a sufficient time period. This might be achieved by co‐culturing hepatocytes with diverse cell lines. However, from one cell line to the other differences in the pattern of stabilization of individual hepatocyte functions are found. In addition, questions on metabolic action of individual isoenzymes can also be addressed by the use of genetically engineered cell lines. All thein vitrosystems mentioned, especially those which contain differentiated human cells or human isoenzymes are helpful in the rational species extrapolation of toxic effects from animal to man.
Effects of Platelet‐Activating Factor Antagonists WEB 2086 and BN 50730 on Digoxin‐Induced Arrhythmias*
Authors: Çakici İcal , Mataraci Neval , Ersoy Sibel , Tunçtan Bahar , Abacioǧlu Nurettin , Kanzik İlker
Published: March 2009

Abstract:Effects of platelet‐activating receptor antagonists WEB 2086 (1.0‐30.0 mg · kg–1intravenously) and BN 50730 (10.0 mg · kg–1intravenously) alone or in combination with CGS 8515 (a specific 5‐lipoxygenase inhibitor, 0.3 mg · kg–1intravenously) and Dazmegrel® (a thromboxane synthase inhibitor, 1.0 mg · kg–1· hr–1intravenous infusion) on digoxin‐induced arrhythmias were investigated in anaesthetised guinea‐pigs. ECG, mean arterial blood pressure, heart rate and arrhythmias were recorded, starting 30 min. before digoxin administration and continuing for 60 min. afterwards. WEB 2086 (10.0 mg · kg–1intravenously) reduced the mortality rate and arrhythmia score significantly compared to the control values. However, in combination with CGS 8515, it did not affect the mortality rate. BN 50730 (10.0 mg · kg–1) reduced the incidence of ventricular fibrillation and also arrhythmia score. BN 50730 in combination with Dazmegrel® was reduced the arrhythmia score, incidence of ventricular fibrillation and mortality rate significantly, compared to control values. Digoxin‐induced acute rise in mean arterial blood pressure was not affected by any of drug treatment except WEB 2086 (10.0 mg · kg–1) in combination with CGS 8515. Heart rate values did not differ between groups. However, pressure‐rate index was reduced by WEB 2086 alone or in combination with CGS 8615. Results showed that although two different platelet‐activating factor antagonists have different effects on the incidence of ventricular fibrillation and mortality, they improved the digoxin‐induced arrhythmias when they were used either separately or in combination with CGS 8515 or Dazmegrel® by implicating that platelet‐activating factor has a role on digoxin‐induced arrhythmias.
Comparison of the Binding Activities of Some Drugs on α2A, α2Band α2C‐Adrenoceptors and Non‐Adrenergic Imidazoline Sites in the Guinea Pig
Authors: Uhlén Staffan , Muceniece Ruta , Rangel Ninfa , Tiger Gunnar , Wikberg Jarl E. S.
Published: March 2009

Abstract:Simultaneous computer modelling of control and guanfacine‐masked [3H]‐MK 912 saturation curves as well as guanfacine competition curves revealed that both α2A‐ and α2C‐adrenoceptor subtypes were present in the guinea pig cerebral cortex. The Kdvalue of [3H]‐MK 912 determined for the α2A‐subtype was 403 pM and for the α2C‐subtype 79.8 pM; the receptor sites showing capacities 172 and 19.5 fmol/mg protein, respectively. The Kdsof guanfacine were 20 and 880 nM for the α2A‐ and α2C‐adrenoceptor, respectively. In the guinea pig kidney [3H]‐MK 912 bound to a single saturable site with Kd8.34 nM and capacity 285 fmol/mg protein, the site showing pharmacological properties like an α2B‐adrenoceptor. Binding constants of 22 compounds for the three guinea pig α2‐adrenoceptor subtypes were determined by computer modelling competition curves using for the cerebral cortex a “3‐curve assay”, for the kidney an “1‐curve assay”, and using [3H]‐MK 912 as labelled ligand. Of the tested drugs guanfacine and BRL 44408 were found to be clearly α2A‐selective. Spiroxatrine, yohimbine, rauwolscine and WB 4101, as well as [3H]‐MK 912 itself, were found to be α2C‐selective. The most selective compounds for α2B‐adrenoceptors, when compared to α2A‐adrenoceptors, were ARC 239 and prazosin. In the guinea pig kidney [3H]‐p‐aminoclonidine bound to α2‐adrenoceptors as well as to non‐adrenergic imidazoline sites. The α2‐adrenoceptors could be completely blocked using 10 μM (‐)‐adrenaline without the non‐adrenergic sites being affected. During these conditions the analysis of combined saturation and competition studies using labelled and unlabeled p‐aminoclonidine with computer modelling revealed that the ligand labelled two different sites with Kdsof 310 and 47,000 nM, respectively. Competition curves of 16 compounds for the non‐adrenergic [3H]‐p‐aminoclonidine sites were shallow and resolved into two‐site fits. For the high affinity [3H]‐p‐aminoclonidine site the highest affinities were shown by 1‐medetomidine, UK‐14,304, guanabenz and detomidine; the Kdsof these drugs ranging 26–72 nM. All drugs tested showed low but varying affinities for the low affinity [3H]‐p‐aminoclonidine site. These data indicated that the [3H]‐p‐aminoclonidine binding sites of the guinea pig kidney are grossly different from the [3H]‐idazoxan binding I2‐receptors previously demonstrated also to be present in the guinea pig kidney.
1a, 25‐Dihydroxyvitamin D3 Decreases Scalding‐and Platelet‐Activating Factor‐Induced High Vascular Permeability and Tissue Oedema
Authors: Chen Si‐Feng , Rnan Yun‐Jun
Published: March 2009

Abstract: We have previously demonstrated that 1, 25‐dihydroxyvitamin D3 decreases endotoxin‐induced mortalities of rat and mouse from 80% and 70% to 14% and 10% (unpublished results). In the present study, pretreatment of 1, 25‐dihydroxyvitamin D3 decreased pad oedema and pulmonary vascular permeability induced by scalding and platelet‐activating factor. 1, 25‐Dihydroxyvitamin D3 in a dose of 4x10–9 mol/kg decreased pulmonary extravascular Evans blue concentration increased by platelet‐activating factor from 6.32 ± 0.63 ng/g to 2.57 ± 0.28 ng/g (P<0.01), and lung water/dry lung weight from 3.79±0.57 to 1.51±0.13 (P<0.01). 1, 25‐Dihydroxyvitamin D3 of 4x10–11 moles/kg and calcipotriol (a vitamin D analogue which has limited hypercalcaemic effect) of 4x10–9 moles/kg had similar effects. Karyocyte counting of bronchoalveolar lavage fluid and the reduction of mean arterial pressure were also reduced to some extent. These results suggest that 1, 25‐dihydroxyvitamin D3 may be a new and effective drug to reduce vascular permeability and ameliorate oedema.
Effects of Long‐Term Antiepileptic Therapy on the Catabolism of Testosterone
Authors: Brunet Mercè , Rodamilans Miquel , Martinez‐Osaba M. Jose , Santamaria Joan , To‐Figueras Jordi , Torra Mercè , Corbella Jacint , Rivera Francisca
Published: March 2009

Abstract:The serum levels of testosterone, sex hormone binding globulin, and free testosterone index were measured in 51 epileptic men (age 18–45) in order to assess the possible effects of antiepileptic drugs on sexual dysfunction. An analytical gas chromatography‐mass spectrometry method was developed to assess the urinary excretion of testosterone, epitestosterone, androsterone, etiocholanolone, 11‐OH androsterone and 11‐OH etiocholanolone and to evaluate if the catabolism of testosterone had been increased. Twenty normal healthy males of similar age, 18–45 years, served as control group. Patients receiving polytherapy (n=34) or monotherapy with carbamazepine (n=8) or phenytoin (n=9) showed higher levels of sex hormone binding globulin and testosterone, and lower levels of free testosterone than did the controls (P<0.03). Urinary excretion of the metabolites androsterone and 11‐OH androsterone was significantly reduced (P<0.02) in the polytherapy group, while the monotherapy group showed only significant differences (P<0.02) in the elimination of 11‐OH androsterone. Our results suggest that an induction of the hepatic synthesis of sex hormone binding globulin may be the mechanism by which the antiepileptic drugs lower the levels of free testosterone in serum. However, the reduced excretion of androsterone and the normal levels of etiocholanolone show that the antiepileptic drugs do not produce an increase in the main catabolism pathway of testosterone.
Role of Ca2+ on Endotoxin‐Sensitivity by Galactosamine Challenge: Lipid Peroxide Formation and Hepatotoxicity in Zymosan‐Primed Mice
Authors: Sakaguchi Shuhei , Yokota Katsushi
Published: March 2009

Abstract: This study was investigated to clarify the role of intracellular Ca2+ following endotoxin treatment (1 mg/kg, intraperitoneally) to D‐galactosamine‐sensitized mice (400 mg/kg, intraperitoneally), and to observe lipid peroxide levels, an index of hepatotoxicity, in endotoxin/galactosamine (Ga1N)‐challenged mice under activation of macrophages, especially Kupffer cells, by zymosan. The liver lipid peroxide level and serum glutamic pyruvic transminase activity in mice 18 hr after administration of endotoxin/Ga1N were markedly higher than those in mice treated only with endotoxin. In spite of an increase in lipid peroxide formation, there was little or no effect of Ga1N administration on xanthine oxidase and superoxide dismutase activities in mice given endotoxin. However, the injection of verapamil (10 mg/kg, subcutaneously) markedly decreased lipid peroxide levels in liver of endotoxin/Ga1N‐injected mice. In the mice given a Ca2+‐deficient diet, lipid peroxide level in liver after endotoxin/Ga1N injection was markedly decreased compared to that in mice fed a normal diet. Administration of dexamethasone (200 μg/kg, intraperitoneally) in mice 1 hr before treatment with endotoxin/Ga1N did not induce lipid peroxide formation. Administration of endotoxin to Ga1N‐treated mice resulted in a higher level of liver cytosolic free Ca2+ ([Ca2+]i) than that in endotoxin‐treated mice. On the other hand, Ca2+‐ATPase activity in liver plasma membrane in the endotoxin/Ga1N‐treated mice was markedly decreased as compared with endotoxin alone. On the contrary, the Ca2+‐ATPase activity in liver mitochondria was higher in endotoxaemic mice treated with Ga1N than in mice given endotoxin alone. State 3 respiration and respiratory control index, which are parameters of mitochondrial function, were decreased more in the liver of mice treated with endotoxin/Ga1N than in the endotoxin‐treated group. These findings suggest that [Ca2+]i may participate in the lipid peroxide formation which results from endotoxin/Ga1N‐induced hepatotoxicity under conditions of zymosan‐activated macrophages, and that the increases of endotoxin‐sensitivity caused by Ga1N challenge may greatly contribute to Ca2+‐mobilization in the hepatocyte.
Presynaptic α2A‐Adrenoceptors Regulate the3H‐Noradrenaline Secretion in the Guinea‐Pig Urethra
Authors: Alberts Pēteris
Published: March 2009

Abstract:The subtype of the functional presynaptic autoreceptor in adrenergic nerves of the male guinea‐pig urethra was pharmacologically characterised. The urethra was incubated with3H‐noradrenaline and superfused with Tyrode solutionin vitroand the fractional secretion of3H‐noradrenaline evoked by 300 electrical shocks at 5 Hz was measured. α‐Adrenoceptor antagonists enhanced the3H‐noradrenaline secretion. The effects of BRL 44408 ((±)‐2‐[(4,5‐dihydro‐1H‐imidazol‐2yl)methyl]‐2,3‐dihydro‐1‐methyl‐1H‐isoindole), BRL 41992 ((‐)‐1,2‐dimethyl‐2,3,9,13b‐tetrahydro‐1H‐dibenzo[c,f]imidazo[1,5‐a]azepine), and WB‐4101 (2‐([2,6‐dimethoxyphenoxyethyl]aminomethyl)‐1,4‐benzodioxane) were tested. The rank order of apparent EC50values was BRL 44408<BRL 41992<WB‐4101, and correlated best with constants for the α2A‐C10/α2Aadrenoceptor subtype. The results suggest that3H‐noradrenaline secretion in guinea‐pig urethra is regulated by a presynaptic adrenoceptor of the α2Asubtype.
Functional Effects of Adrenochrome in Isolated Rabbit Heart
Authors: Rump A. F. E. , Klaus W.
Published: March 2009

Abstract: The cardiotoxic effects of catecholamines have been explained in part by the generation of oxygen free radicals and aminochromes. The role of aminochromes remains however controversial. It has previously been demonstrated that adrenochrome, an oxidation product of adrenaline, shows cardiotoxic properties only at very high concentrations, and it has been suggested that the deleterious effects observed may be caused by a worsening in myocardial perfusion. The functional properties of adrenochrome were examined in isolated spontaneously‐beating rabbit hearts with depleted catecholamine stores (reserpin 7.0 mg/kg 16–24 hr before preparation, Langendorff, constant pressure: 70 cm H2O, Tyrode solution, [Ca++]sol 1.8 mmol/l, 37°). Cumulative concentration‐response curves show an adrenochrome‐concentration‐dependent increase of contractility (left ventricular pressure, EC50 = 3.6×10‐6 M; +dp/dtmax, EC50 = 1.6×10‐5 M), whereas myocardial relaxation was impaired (‐dp/dtmax, EC50 = 2.6×10‐5 M; ‐dp/dtmax/+dp/dtmax = 0.68 at 10‐4 M). Heart‐rate was only slightly enhanced (+10% at 10‐4 M), and the coronary flow was markedly influenced only by adrenochrome 10‐4 M (‐17%). The relative coronary flow (=global coronary flow/pressure‐rate product) was concentration‐dependently reduced (EC50 = 10‐5 M; −49% at 10‐4 M). We conclude that in isolated rabbit hearts, adrenochrome has a positive inotropic action but impairs myocardial relaxation, and coronary constrictor activity prevents an increase of myocardial oxygen supply, thus worsening myocardial oxygen‐demand/supply balance.
Metabolism is an Important Route of Pentamidine Elimination in the Rat: Disposition of14C‐Pentamidine and Identification of Metabolites in Urine Using Liquid Chromatography‐Tandem Mass Spectrometry
Authors: Bronner Ulf , Ericsson Örjan , Nordin Jan , Wikstrωm Inger , Abdi Yakoub Aden , Hall James Edwin , Tidwell Richard R. , Gustafsson Lars L.
Published: March 2009

Abstract:This study assesses the contribution of metabolism for the disposition of pentamidine in the rat. With the use of14C‐labelled compound, the excretion of radioactivity in urine and faeces has been studied in four rats during 44 days after a single intravenous injection of the drug. The urinary and faecal excretion of the radioactivity were of equal importance; 22±2% (mean±S.D.) and 25±4% being detected in urine and faeces, respectively. The activity in organs and tissues at 44 days after drug administration was also measured and amounted to 21±5% of the administered dose. Using HPLC the proportion of metabolites in urine in relation to unchanged pentamidine increased with time after dose, being 76±15% (mean±S.D.) of the total excreted radioactivity on day 1 and 97±1% on day 6. HPLC ‐ tandem mass spectrometry was used for identification of metabolites in urine obtained from four rats given unlabelled pentamidine. Using synthetic reference compounds and the selective MS/MS mode four oxidized metabolites of pentamidine were identified either by direct injection into the system or by analyses of extracted urine. Thus, a substantial part of pentamidine is excreted as metabolites in urine.
Differences in Hepatic Drug Metabolizing Enzymes and their‐Response to Lindane in Rat, Rabbit and Monkey
Authors: Puri S. , Kohli K. K.
Published: March 2009

Abstract:Untreated rabbit liver microsomes demonstrated the highest content of cytochrome P450 and activity of NADPH cytochromecreductase compared to rat and monkey. The sodium dodecyl sulfate polyacrylamide gel electrophoresis of microsomes from untreated rabbit demonstrated a greater quantity of 50 KDa polypeptide than in rat and monkey. The activity of glutathione‐S‐transferase towards 1‐chloro‐2,4‐dinitrobenzene and the band intensity of 26 KDa polypeptide was found to be at maximum in untreated rabbits, while rat liver demonstrated the highest activity of glutathione‐S‐transferase towards ethacrynic acid. The extent of hepatic microsomal lipid peroxidation was at maximum in untreated rats. The activity of catalase was higher in untreated monkeys compared to untreated rats and rabbits. Lindane at a dose of 10 mg kg‐1body weight for a period of six days increased the hepatic content of cytochrome P450 and the activities of NADPH cytochromecreductase, aminopyrine N‐demethylase, glutathione‐S‐transferases, haem oxygenase and lipid peroxidation, decreased non‐protein thiols and concomitantly intensified the 50 and 26 KDa polypeptides in the microsomes and 100,000xg supernatants respectively, in the rat but not in the rabbit or monkey. The results demonstrate that lindane is a bifunctional inducer in the rat and non‐functional in rabbit and monkey. It also increased the activities of hepatic drug metabolizing enzymes with concomitant production of oxidative stress in the rat, whereas in rabbit and monkey it did not alter the drug metabolizing enzymes nor produced any oxidative stress.
Transfer of Lidocaine and Bupivacaine Across the Isolated Perfused Human Placenta *
Authors: Ala‐Kokko Tero I. , Pienimäki Päivi , Herva Riitta , Hollmén Arno I. , Pelkonen Olavi , Vähäkangas Kirsi
Published: March 2009

Abstract: Drug permeability and pharmacokinetics through the placenta are important factors determining foetal drug exposure. The purpose of the present study was to establish a perfused human placental cotyledon system to assess the placental transfer of lidocaine and bupivacaine, widely used local anaesthetics in obstetric anaesthesia. Term placentas were obtained immediately after delivery with maternal consent and a two‐hour recycling perfusion of a single placental cotyledon was performed. Bupivacaine or lidocaine with antipyrine as a reference compound were added to the maternal reservoir and their disappearance from the maternal circulation and appearance to the foetal circulation were followed in five experiments for each drug. Drug concentrations were measured by gas chromatography. Bupivacaine disappeared more rapidly from the maternal circulation than lidocaine. At 2 hr, bupivacaine foetal:maternal concentration ratio was 0.56±0.12 and 14.6%±2.99 of the total circulating amount was found in the foetal circulation. Lidocaine concentration increased more in the foetal circulation and the foetal: maternal concentration ratio at 2 hr was 0.90±0.09 (P<0.01), and 22.1%±2.21 (P<0.01) was found in the foetal circulation. The maternal to foetal transfer of bupivacaine and lidocaine were 67.2%±0.153 and 98.9%+0.07 (P<0.05) of that of freely diffusable antipyrine, respectively. Both amide local anaesthetics crossed the dually perfused human placenta rapidly. Bupivacaine disappeared faster than lidocaine from the maternal circulation but less was transferred to foetal circulation. This difference is probably explained by the greater lipophil‐icity of bupivacaine and hence higher placental binding. These results suggest less foetal drug exposure with bupivacaine than lidocaine.
Interaction of 3,4,5,3′,4′‐Pentachlorobiphenyl and 2,4,5,2′,4′,5′‐Hexachlorobiphenyl in Promotion of Altered Hepatic Foci in Rats
Authors: Bager Yvonne , Hemming Helena , Flodström Sten , Ahlborg Ulf G. , Wärngård Lars
Published: March 2009

Abstract: This study was undertaken to investigate tumour promoting interactions of 2,4,5,2′,4′,5′‐hexachlorobiphenyl (PCB 153) and 3,4,5,3′,4′‐pentachlorobiphenyl (PCB 126) in female Sprague‐Dawley rats. Five weeks before the promotion treatment, the rats were partially hepatectomized and initiated with nitrosodiethylamine. The test substances were administered by weekly, subcutaneous injections for 20 weeks. The results from this study suggest that treatment with a combination of these two congeners causes a more than additive effect on the formation of γ‐glutamyltranspeptidase‐positive hepatic foci. Co‐exposure to PCB 126 and PCB 153 caused a dose‐dependent reduction of the PCB 153‐induced CYP2B1/B2‐activity in these livers.
Nephrotoxicities of Aluminium and/or Cadmium‐Metallothionein in Rats: Creatinine Excretion and Metabolism of Selected Essential Metals
Authors: Liu Jenny X. , Nordberg Gunnar F.
Published: March 2009

Abstract:The effects of exposure to aluminium (Al) and cadmium (Cd) on urinary creatinine and protein excretion, and the concentrations of calcium, magnesium and copper in kidney and urine were studied in 32 male adult Wistar rats. The animals were divided into 8 groups, groups 1–4 given a calcium‐deficient diet (0.01%, i.e. 0.01 g calcium/100 g diet weight) and groups 5–8 a calcium‐adequate diet (0.9%) for 6 weeks. Single daily intraperitoneal injections of AlCl3(10.8 mg Al/kg body weight, per day) were done on 6 consecutive days to groups 3, 4, 7 and 8 during the last week of the experiment. One single intraperitoneal injection of cadmium‐metallothionein (Cd‐MT, 0.4 mg Cd/kg) was administered 12 hr before the final Al dose to groups 2, 4, 6, and 8 and the rats were sacrificed 47 hr after the Cd‐MT injection. The rate of creatinine clearance was significantly lower in rats injected intraperitoneally with either Cd‐MT or Al, and the concentrations of magnesium and calcium in urine were lower in rats administered both Al and Cd‐MT as compared to those in control groups. Histological examination showed that Al was toxic to the kidney tubule cells of rats, however, an adequate supply of calcium in food protected to some extent the renal tubules from Al toxicity as indicated by a higher creatinine clearance, and there was also less tubule damage as shown by histological examination. The copper concentrations in kidney tissue were lower in groups treated with either Al or Cd‐MT. The above results indicate that: (1) Al administered by intraperitoneal injection is nephrotoxic in rats; (2) food deficient in calcium increases the vulnerability of the kidney to Al‐induced toxicity; (3) the decreased creatinine clearance in Cd‐MT‐injected rats may explain the low calcium excretion in urine observed in these rats.
Effect of Chronic Diazepam Treatment on Footshock‐Induced Ultrasonic Vocalization in Adult Male Rats
Authors: Nielsen Christina Kurre , Sánchez Connie
Published: March 2009

Abstract: Rats were tested in the footshock‐induced ultrasonic vocalization model of anxiety. The ultrasounds were recorded 1–11 min. after 10 inescapable 0.6 mA footshocks each of 1 sec. duration. Repeated administration of benzodiazepines in the clinic has been reported to be accompanied by development of tolerance and withdrawal anxiety. The present study examined whether the ultrasonic vocalization model could reflect these two side effects. Diazepam 4.6 or 8.8 μmol/kg (1.3 or 2.5 mg/kg, subcutaneously) administered twice a day (8 a.m. and 4 p.m.) abolished the vocalization after acute administration and after 3 weeks of treatment. Hence, no tolerance developed to the anxiolytic effect of diazepam. When the rats were tested 24 and 48 hr after the last doses of diazepam there were no significant differences from the control group, i.e. no apparent withdrawal anxiety. Instead, the control groups developed tolerance to the shock regimen during the chronic experiments. This was examined further by daily testing of a group of naive rats for 13 days. The findings indicated that there is a limitation in number of test sessions before tolerance to the model develops. In conclusion, the results of the present study contribute to the many contradictory and by no mean unequivocally findings in the literature. It indicates that substantial prediction of anxiolytic effects as well as unwanted side effects cannot be made from one single test model.
Effects of Selective Opioid Receptor Antagonists on Morphine‐Induced Changes in Striatal and Limbic Dopamine Metabolism
Authors: Piepponen T. Petteri , Ahtee Liisa
Published: March 2009

Abstract:The effects of selective opioid receptor antagonists, β‐funaltrexamine (selective for μ receptor), naloxonazine (μl) and naltrindole (δ) on morphine‐induced changes in striatal and limbic dopamine (DA) metabolism were studied in rats. β‐Funaltrexamine (20 μg intracerebroventricularly) and naloxonazine (15 mg/kg intraperitoneally) were given 24 hr before morphine (15 mg/kg subcutaneously), and the rats were decapitated 60 min. after morphine. Naltrindole (1 mg/kg intraperitoneally) was given twice, 15 min. before and after morphine. Morphine significantly increased the concentrations of DA metabolites 3,4‐dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This effect was significantly antagonized by pretreatment with β‐funaltrexamine but not by naloxonazine or naltrindole. However, naloxonazine attenuated the antinociceptive effect of morphine in the hot‐plate test. The concentration of DA was not significantly altered by any of the drugs studied. These results show that selective blockade of μ‐opioid receptors totally blocks the increase of striatal and limbic DA metabolism induced by morphine. It seems that μ2‐subtype of μ‐opioid receptor predominantly mediates this effect. Blockade of δ‐opioid receptor did not alter these effects of morphine.
The Effect of Nicotine and Its Interaction with Carbon Tetrachloride in the Rat Liver
Authors: Yuen Siu Tsan , Gogo Arturo R. , Luk Ivy S. C. , Cho Chi Hin , Ho Joana C. I. , Loh Tatt T.
Published: March 2009

Abstract:In order to study the effects of nicotine on liver, groups of rats were given nicotine doses that simulated those seen in chronic smoking (54 and 108 μmol/l of nicotine) for 10 days. A subgroup was also given a single subcutaneous injection of 6 g/kg of carbon tetrachloride (CCl4) shortly before the animals of the group were killed. Histology demonstrated a significant hepatotoxic effect in the group receiving 108 μmol/l of nicotine when compared with the control group in the form of fatty change, focal or confluent necrosis and dark‐cell change. The effects in pregnant rats were less severe. Carbon tetrachloride alone induced significant fatty change and focal necrosis in non‐pregnant rats but not in pregnant rats. Nicotine also aggravated the CCl4induced pathological changes in livers of both non‐pregnant and pregnant animals. Thus nicotine alone, when given at a concentration of 108 μmol/l, exerted hepatotoxic effects; the alkaloid also aggravated the hepatotoxicity of CCl4. Pregnant rats were more resistant to the hepatotoxic effects produced by nicotine and CCl4.
Action of Reactive Oxygen Species and Their Antagonists on Twitch Tension of the Rat Phrenic Nerve‐Diaphragm
Authors: Crosland Richard D.
Published: March 2009

Abstract:Reactive oxygen species have been implicated in normal and pathological processes of many tissues, including skeletal muscle. I extended previous studies by examining the effect of these intermediates and eight of their antagonists (superoxide dismutase, catalase, deferoxamine, [Cu(II)]2(3,5‐diisopropylsalicylate)4, 1,2‐dimethyl‐3‐hydroxy‐pyridone, 1,3‐dimethyl‐2‐thiourea, N‐(2‐mercaptopropionyl)‐glycine, vitamin E) on indirectly stimulated twitch tension of anin vitroneuroskeletomuscular preparation, the phrenic nerve‐diaphragm of the rat. In the absence of exogenous reactive oxygen species, none of the antagonists potentiated twitch tension, and all but one (N‐[2‐mercaptopropionyl]‐glycine) of the membrane‐permeant antagonists attenuated twitch tension. The reactive oxygen intermediate‐generating system of purine plus xanthine oxidase reduced indirectly stimulated twitch tension by 36% while having no effect on directly stimulated twitch tension. Catalase (but not superoxide dismutase or deferoxamine) eliminated the reduction in twitch tension, indicating that hydrogen peroxide played a role in the reduction. The membrane‐permeant antagonists [Cu(II)]2(3,5‐diisopropylsalicylate)4and 1,2‐dimethyl‐3‐hydroxy‐pyridone also eliminated the reduction in twitch tension caused by reactive oxygen species, suggesting that hydrogen peroxide could have acted intracellularly through an iron‐catalyzed Haber‐Weiss reaction to produce hydroxyl radical, which in turn reacted with intracellular components, thereby reducing twitch tension.
Microsomal Function in Hepatitis B Surface Antigen Healthy Carriers: Assessment of Cytochrome P450 1A2 Activity by the 14C‐Caffeine Breath Test
Authors: Horsmans Y. , De Koninck X. , Geubel A. P. , Pauwels S.
Published: March 2009

Abstract: The hepatitis B surface antigen (HBsAg) carrier state is associated with changes in hepatocellular function involving the cytochrome P450 (CYP) system. Among this system, CYP1A2 enzyme plays an important role in chemical carcinogenesis and in the metabolism of several drugs. We have thus investigated CYP1A2 function using two 14C‐caffeine breath tests (3‐methyl‐14C; C3BT and 7‐methyl‐14C caffeine; C7BT) in 12 HBsAg healthy carriers and 8 healthy volunteers matched for 14C‐aminopyrine breath test values. HBsAg carriers exhibited lower C3‐ and C7BT values than normal controls. This difference, however, did not reach statistical significance except for C7BT values normalised for aminopyrine breath test values. Our data thus do not support the association between viral presence and CYP1A2 dysfunction.
Prevention of Class III‐Induced Proarrhythmias by Flecainide in an Animal Model of the Acquired Long QT Syndrome
Authors: Hallman Katarina , Carlsson Leif
Published: March 2009

Abstract:The influence of the class Ic agent, flecainide, on the incidence of class III‐induced torsades de pointes was examined in an animal model of the acquired long QT syndrome. Twenty‐four chloralose‐anaesthetized rabbits were pretreated at random with flecainide or vehicle and subsequently given a concomitant infusion of methoxamine and the class III antiarrhythmic agent almokalant. In seven out of eight vehicle‐treated rabbits, almokalant induced torsades de pointes which was preceded by a significant lengthening of the JTU interval (used as an indirect measure of ventricular repolarization time) by 55±9.2 msec. Flecainide dose‐dependently reduced the incidence of almokalant‐induced torsades de pointes. Hence, in a group of rabbits given a low dose (0.14 μmol/kg+1.4 μmol/kg/hr) of flecainide, four out of eight animals experienced torsades de pointes (P=0.1538 versus vehicle) whereas no case (n=8) was observed after a higher dose (4.8 μmol/kg+4.8 μmol/kg/hr, P=0.0007). In the former group almokalant induced a maximal increase in the JTU interval not differing from that seen in the vehicle‐treated group (58+12.1 msec, P>0.05). Pretreatment with the high dose of flecainide, however, caused a significant attenuation of the almokalant‐induced lengthening of the JTU interval (18±6.5 msec. P<0.05). It is concluded that flecainide reduces the risk of proarrhythmia in the setting of delayed repolarization partially by attenuating the primary electrophysiological effect of class III agents.
Effects of Misoprostol on Circulating HDL‐Cholesterol, Total Cholesterol, Triglycerides and their Relationship with Hepatic Microsomal Function
Authors: Godinho A. F. , Silva M. A.
Published: March 2009

Abstract:The effects of misoprostol (cytotec, SC29333) on circulating lipoproteins and liver microsomal enzyme activity were studied. Misoprostol increased serum levels of high density lipoprotein‐cholesterol and decreased total cholesterol and triglycerides. The high density lipoprotein‐cholesterol/total cholesterol ratio increased by 54.8%. In parallel, misoprostol significantly altered enzyme hepatic activity. Liver microsomal cytochromes P450 and b5were significantly increased in correlation with enhanced liver aminopyrine N‐demethylase and antipyrine hydroxylase activities, suggesting a liver induction effect of misoprostol. Other observations such as increased liver weight and glycogen and increased plasma albumin and glucose in rats receiving misoprostol support this evidence.
Estimation of the Convulsive Effect of Cyanide in Rats
Authors: Cassel Gudrun E.
Published: March 2009

Abstract: Convulsions are frequently observed in severe, acute cyanide intoxication. The mechanisms involved are not well known. In the present study, the convulsive effect of cyanide was examined in the rat by means of a dose threshold determination after infusion of cyanide. An optimal dose rate of 1.80 mg/min./kg was determined. By infusing this optimal dose rate it was possible to divide another cyanide‐treated group of rats into two groups: one without and another with convulsions. After the experiment all animals were killed by exposure to high intensity microwave irradiation. Regional dopamine, noradrenaline and main dopamine metabolites were isolated and analyzed using high pressure liquid chromatography and electrochemical detection. Striatal noradrenaline was decreased but dopamine and its metabolites were increased in rats infused with cyanide at the optimal dose rate until the convulsions started. Animals infused with the threshold dose at the optimal dose rate did not show any significant changes in noradrenaline or in dopamine metabolites, but all animals showing convulsions also had increased striatal dopamine levels. Thus changes in dopamine appear to be dependent on convulsions.
3,3′,4,4′‐Tetrachlorobiphenyl Effects on Antioxidant Enzymes and Glutathione Status in Different Tissues of Rainbow Trout
Authors: Otto Diana M. E. , Moon Thomas W.
Published: March 2009

Abstract:Polychlorinated biphenyls are known to cause induction in cytochrome P450‐dependent monooxygenase activities and alteration in the antioxidant defense of mammals. To determine whether similar detoxication processes are activated in rainbow trout (Oncorhynchus mykiss), we investigated P450‐dependent enzyme activities, antioxidant enzymes and glutathione status (reduced and oxidized glutathione, GSH and GSSG) in this species injected intraperitoneally with 3,3′,4,4′‐tetrachlorobiphenyl at 5 mg/kg body weight 6 weeks post injection. Ethoxyresorufin O‐deethylase activities increased 11‐ and 40‐fold in liver and kidney, UDPglucuronosyltransferase activities were 2‐ and 5‐fold higher in these organs, while glutathione S‐transferase activity was enhanced greater than 2‐fold in liver of tetrachlorobiphenyl injected trout in comparison with controls. Glutathione peroxidase activities were increased in liver and white muscle of dosed fish. Tetrachlorobiphenyl exposure resulted in a significant increase in glutathione reductase activities, with 7‐fold enhancement in liver and significantly elevated activities in kidney, red and white muscles. Similarly, cytosolic superoxide dismutase and catalase activities were increased in white muscle of injected trout. Tetrachlorobiphenyl exposure significantly increased GSH concentrations in liver and kidney, while GSSG levels were increased in liver and blood plasma. These changes, however, did not modify the GSSG/GSH ratios in these tissues. Overall, these results imply a major tetrachlorobiphenyl effect on GSH status and antioxidant enzymes in trout tissues and identify white muscle along with liver and kidney as important tissues in the detoxication process in this animal.
Proliferation of Hepatocytes and Attenuation from Carbon Tetrachloride Hepatotoxicity by Gadolinium Chloride in Rats
Authors: Ishiyama Hironobu , Sato Makoto , Matsumura Kuniko , Sento Miwa , Ogino Keiki , Hobara Tatsuya
Published: March 2009

Abstract:Intravenous injection of gadolinium chloride (GdCl3) at a dose of 10 mg/kg caused an increase in proliferating cell nuclear antigen labeling index and the grade of pyronin positivity (RNA level) in rat liver. In CCl4‐exposed rats, pretreatment with GdCl3also showed a preventive effect of the liver injury both biochemically and histologically. Moreover, the proliferative action preceded the attenuative effect of the liver injury. Results suggest that GdCl3induces hepatocyte proliferation, and this action of GdCl3may modify the development of CCl4‐induced liver injury.
Effects of Cholecystokinin Receptor Agonist and Antagonists on Morphine Dependence in Mice
Authors: Zarrindast Mohammad‐Reza , Malekzadeh Anahita , Rezayat Mehdi , Ghazi‐Khansari M.
Published: March 2009

Abstract:In the present study, the effect of cholecystokinin agonists and antagonists on dependence to morphine in mice has been investigated. Mice were treated subcutaneously with morphine (50, 50 and 75 mg/kg) three times daily for 2–4 days, and a last dose of morphine (50 mg/kg) was administered on day 3, 4 or 5. Withdrawal syndrome (jumping) was precipitated by naloxone (2.5, 5 and 10 mg/kg) which was administered intraperitoneally 2 hr after the last dose of morphine. To study the effects of cholecystokinin receptor agonists or antagonists, 10 injection of morphine (3 administrations each day) for dependence and a dose of 5 mg/kg of naloxone for withdrawal induction were employed. Cholecystokinin‐8 (0.001–0.01 mg/kg), low doses of the cholecystokinin agonists caerulein (0.00001 and 0.0001 mg/kg) and, unsulfated cholecystokinin (but not high doses) as well as the antagonists MK‐329 (0.5–1 mg/kg) and L‐365,260 (0.5–1 mg/kg) elicit reduction of the nalaxone‐induced jumping. The inhibition of jumping induced by caerulein was reduced with the selective cholecystokinin antagonists MK‐329 and L‐365,260. It is concluded that cholecystokinin mechanism(s) may be involved in morphine dependence, that the agonists may act on a presynaptic receptors and that the antagonists may work on postsynaptic receptors.
Selective Blockade of Leukotriene Production by a Single Dose of the FPL 64170XX 0.5% Enema in Active Ulcerative Colitis
Authors: Kjeldsen Jens , Laursen Laurits Stærk , Hillingse Jens , Mertz‐Nielsen Anette , Bukhave Klaus , Rask‐Madsen Jørgen , Lauritsen Karsten
Published: March 2009

Abstract: 5‐Lipoxygenase products of arachidonic acid metabolism are thought to play a central role in the secondary amplification of the inflammatory response of several inflammatory diseases, including ulcerative colitis. FPL 64170XX is a selective inhibitor of the enzyme 5‐lipoxygenase. Concentrations of leukotriene B4 and prostaglanding E2 in rectal dialysis fluid from 23 males with clinically and sigmoidoscopically active, distally located ulcerative colitis were measured by radioimmunoassays in a double‐blind, placebo‐controlled, parallel design study before and after rectal administration of an enema containing 0.5% of FPL 64170XX. Repeated measures analysis of leukotriene B4, after adjusting for baseline, showed a significant treatment effect (P=0.0014). The concentration of leukotriene B4 from rectal dialysates in patients receiving the active drug dropped to 15% (95% confidence interval 5–40%) of the placebo level in the second dialysis following administration of FPL 64170XX 0.5%. By contrast, prostaglanding E2 concentrations doubled (P=0.0068) in patients receiving FPL 64170XX 0.5% with no change in the placebo group. These findings demonstrate that a single dose of FPL 64170XX 0.5% enema selectively blocks the generation of the 5‐lipoxygenase product, leukotriene B4, to a mean of 85% in the target tissue of inflammation. Topical administration of this new leukotriene synthesis inhibitor may prove to be a clinically useful approach to the treatment of active, distally located ulcerative colitis.
Lipid Changes in Plasma and Blood Cells Following Intravenous 10% Fat Infusion in Man
Authors: Wang Wen‐Qi , Xu Ning , Gustafson Anders
Published: March 2009

Abstract: The effects of a 500 ml 4 hr infusion of 10% fat emulsion (Lipovenös®) on the lipid content of plasma lipoproteins and blood cells, and on the platelet aggregation rate, were studied in ten volunteers. The infusion resulted in a significant (P<0.05) initial increase in plasma total triglycerides (more than 5 times), phospholipids (28.7%) and free cholesterol (43.3%), but a decrease in the free cholesterol content of erythrocytes and mononuclear cells (by 4.4% and by 22.7%, respectively). Plasma cholesteryl ester was reduced by 18.2% after the infusion, most of the reduction being accounted for by the 16.5% reduction in high‐density lipoproteins. Our findings suggest more than 35% of the free cholesterol accumulated in plasma to derive from peripheral tissues, in turn suggesting overall reverse cholesterol transport from peripheral tissues to plasma to be enhanced. Post‐infusion platelet aggregation in response to adenosine disphophate was significantly reduced, the peak rate by 31% and 1 min. rate by 20.6% (P<0.05 in both cases). These changes in plasma lipids found in normal volunteers suggest that a short‐term intravenous infusion of 10% Lipovenös might also be beneficial in preventing atherosclerosis.
A Comparison of Two Oximes (HI‐6 and Obidoxime) for 2‐Dimethylaminoethyl‐(dimethylamido)‐phosphonofluoridate Poisoning
Authors: Kassa J.
Published: March 2009

Abstract:The effects of HI‐6 (1‐[[[(4‐aminocarbonyl) pyridinio]methoxy]methyl]‐2‐(hydroxyimino)‐methyl]pyridinium dichloride monohydrate) on the organophosphorus agent 2‐dimethylaminoethyl‐(dimethylamido)‐phosphonofluoridate (GV) inhibited cholinesterases in blood, brain and diaphragm and the stressogenic effect of GV in rats were compared to the effects of obidoxime. In GV‐poisoned rats, HI‐6 had a significantly higher reactivating effect in blood and brain as well as diaphragm than had obidoxime. HI‐6 also practically eliminated the stressogenic effect of the GV compound. On the other hand, hypercorticosteronaemia and increase of liver tyrosine aminotransferase activity during treatment of poisoning with obidoxime were observed. These findings demonstrate the importance of HI‐6 for treatment of GV agent poisoning in rats.
The Contribution of Lysosomal Trapping in the Uptake of Desipramine and Chloroquine by Different Tissues
Authors: Daniel W. A. , Bickel M. H. , Honegger U. E.
Published: March 2009

Abstract:Cationic amphiphilic drugs strongly accumulate in tissues of different organs. Uptake is controlled by two major mechanisms, non‐specific binding to membrane phospholipids, and ion‐trapping within acidic cellular compartments. The aim of this study was to assess the individual contributions of these two mechanisms on the uptakein vitroof desipramine and chloroquine into tissue slices of control and desipramine‐treated rats. Drug uptake into intact slices was compared with uptake into slices with destroyed or non‐functional acidic compartments. The sequence of desipramine uptake by tissue slices of eight different organs was: lungs>brain>heart>diaphragm>kidneys>skeletal muscles>adipose tissue>liver. The low desipramine concentration in liver may be due to metabolism of the parent drug by cytochrome P‐450. Uptake of chloroquine differed widely between slices of different organs with the sequence: lungs>kidneys=brain=liver>diaphragm=heart=skeletal muscles>adipose tissue. Destruction or inactivation of the acidic compartments by homogenization and freeze‐thawing or by ammonium chloride, sodium fluoride, or monensin, reduced drug uptake to similar extents. The reduction was organ‐specific and may represent the size of the lysosomal compartment in the respective tissue cells. Uptake of chloroquine was more affected than that of desipramine, suggesting that ion‐trapping is the main factor for chloroquine accumulation, while binding to membrane phospholipids, is the main factor for desipramine uptake. Single or multiple‐dose treatments of rats with desipramine hardly had any effect on consecutive desipramine uptake into lung and liver slices, while the accumulation of chloroquine was enhanced in these slices. In conclusion, the extent of uptake of cationic amphiphilic drugs into tissue slices was tissue‐specific, and the contribution of the two uptake mechanisms was strongly drug‐dependent.