bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Some Chelating Agents on the Uptake and Distribution of 54Mn(II) in the Brown Trout (Salmo trutta)
Authors: Rouleau Claude , Tjälve Hans , Gottofrey James , Pelletier Émilien
Published: March 2009

The effects of humic acids, which are natural metal‐complexing compounds, and potassium ethylxanthate, sodium diethyldithiophosphate, sodium dimethyldithiocarbamate, and sodium diethyldithiocarbamate, which are sulphur‐containing man‐made chelating agents, on the uptake and tissue distribution of 54Mn(II) were studied in brown trout (Salmo trutta). Fish were exposed for 7 days to 0.1 μg Mn(II) · 1−1 as MnCl2 (1 μCi 54Mn · l−1) with or without chelating agents. Examination of the partition of Mn between octanol and a Tris‐HCl buffer in the presence of these compounds was also performed. Humic acids had only small effects on Mn uptake and distribution in trout, probably because of the low stability of Mn‐humate complexes. Partition of Mn in the presence of potassium ethylxanthate, sodium diethyldithiophosphate, sodium dimethyldithiocarbamate, and sodium diethyldithiocarbamate between octanol and Tris‐HCl buffer showed formation of lipophilic complex with the latter two compounds, but not with the former. However, these four chelating agents all decreased Mn uptake in the trout by 40‐45%. These substances also changed the distribution of Mn within the fish, with a higher proportion of the metal being present in some visceral organs and a smaller proportion being localized in some non‐parenchymateous tissues, such as skin, fins and bones. The mechanisms underlying these effects are not known. However, the interaction of chelating agents with the Mn, although weak, may have partially withdrawn the metal from the uptake process in the gills. The redistribution of Mn in the fish may be due to the binding of the metal to complexing compounds which have reached the intestinal lumen. Previous studies with other metals have shown increased or unchanged metal levels in tissues of fish at exposure together with potassium ethylxanthate, sodium diethyldithiophosphate, sodium dimethyldithiocarbamate, and sodium diethyldithiocarbamate, but decreased metal levels have not been observed before.
Effects of Diethyldithiocarbamate on Activating Mechanisms of Neutrophils
Authors: Izumi Yukie , Ogino Keiki , Murata Tomoko , Kobayashi Haruo , Hobara Tatsuya
Published: March 2009

The effects of diethyldithiocarbamate on superoxide release by rat neurophils were investigated in a chemiluminescence study. Diethyldithiocarbamate augmented lucigenin‐dependent chemiluminescence in a concentration‐dependent manner and inhibited luminol‐dependent chemiluminescence at concentrations of 0.1‐1 μM. In contrast, after the addition of 0.1 mM diethyldithiocarbamate, the chemiluminescence was markedly enhanced. Diethyldithiocarbamate inhibited both the myeloperoxidase activity of neutrophils and the chemiluminescence generated in a cell‐free horseradish peroxidase/H2O2and H2O2/HOCl system. The increase in lucigenin‐dependent chemiluminescence brought about by diethyldithiocarbamate was inhibited by H‐7, ML‐7, W‐7, EGTA and pertussis toxin. These results suggest that diethyldithiocarbamate may stimulate O2−production by a guanosine 5′‐triphosphate protein‐mediated and Ca2+–dependent process and that the increase in O2−release by neutrophils may be dependent not only on the direct stimulation of the signal transduction pathway but also on the increase in O2−by reducing the effect of the hydroperoxide (H2O2)‐myeloperoxidase system.
Dose‐Dependent Effects of Zinc Supplementation During Chelation of Lead in Rats
Authors: Flora S. J. S. , Bhattacharya R. , Sachan S. R. S.
Published: March 2009

Dose‐dependent effects of zinc supplementation in order to enhance the efficacy of calcium disodium EDTA in lead intoxicated rats was investigated in rats. The results suggest simultaneous supplementation of zinc at a lower concentration i.e. 10 mg/kg (orally, once during chelation treatment), 25 mg/kg zinc (Flora & Tandon 1990) potentiates the mobilization of lead from blood and soft tissues. However, at a higher dose level (50 mg/kg once orally) it has deleterious and much reduced ability to deplete tissue lead contents and restore altered lead sensitive biochemical variables.
Effects of Quinidine on Renal Biochemistry and Function in Young and Old Rats
Authors: Sambasiva Rao , Arvind Agarwal
Published: March 2009

Nephrotoxic effects of qunidine in male Fischer‐344 rats in ages of 3‐4 months and 20‐22 months were evaluated. Renal cortical slice oxygen consumption, accumulation of p‐aminohippurate and tetraethyl ammonium were inhibitedin vitro. No age‐related differences were observed. Quinidine decreased respiratory control index and ADP/O ratio in both age groups. Quinidine administration at 75 mg/kg/day for four days reduced tetraethylammonium transport in both young and old. Blood urea nitrogen increased in the old, but not in the young rats. Serum creatinine levels were elevated in both age groups. Renal cortical slice oxygen consumption decreased in the young but not in the old rats after quinidine administration. No changes in RCI or ADP/O ratio were observed in the two age groups. The results indicate that Fischer‐344 rats in the ages of 20‐22 months are not increasingly susceptible to quinidine‐induced nephrotoxicity.
Pharmacokinetics of a Single Oral Dose of Clobazam in Patients with Liver Disease
Authors: Monjanel‐Mouterde Suzanne , Antoni Michel , Bun Hot , Botta‐Frindlund Danielle , Gauthier André , Durand Alain , Cano Jean Paul
Published: March 2009

The pharmacokinetic effect of a single oral in dose of 20 mg clobazam was studied in 15 patients with liver disease and in 6 healthy volunteers. Plasma concentrations of clobazam and its main metabolite, norclobazam, were measured by gas liquid chromatography. Clobazam was rapidly absorbed. Peak plasma concentrations were 350 + 63 ng/ml at 1.7+0.8 hr in healthy volunteers, 239 + 70 ng/ml at 3 + 1.9 hr in patients with viral hepatitis and 240 + 113 ng/ml at 2.5 + 1.5 hr in patients with cirrhosis. Total distribution volume was 173 + 88 1 and 168 + 71 1 in patients with viral hepatitis and cirrhosis respectively, and 81 + 20 1 in volunteers. Corresponding half‐life values were 47 + 18 hr and 51 + 21 hr in patients and 22 + 6.3 hr in volunteers. The difference between patients was not significant, whereas the differrence between patients and volunteers was significant.
The Present Knowledge of the Inflammatory Process and the Inflammatory Mediators
Authors: Leirisalo‐Repo Marjatta
Published: March 2009

Abstract Endothelial damage, synovial oedema, fibrin deposition, polymorphonuclear cell (PMN) invasion, and mild lining cell hyperplasia characterize acute inflammatory arthritis. Later on, perivascular tissue is infiltrated by mononuclear cells. The early events are mediated by interactions between PMNs and endothelial cells. Both parts in the adhesion event are activated with multiple stimuli resulting in complex interactions of varying intensity and duration. Adhesion molecules present on the surface of PMNs (L‐selectin) or induced by inflammatory stimuli (β2‐integrins) mediate PMN adhesion to activated endothelium, which has counter receptors (E‐selectin for L‐selectin and ICAM‐1 and ICAM‐2 for β2‐integrins). At the initial phase L‐selectin initiates the rolling of PMNs on endothelial cells. Further stimuli result in a more prolonged adhesion between PMNs and endothelium. At the side of endothelium, induction of P‐selectin and PAF by histamine, thrombin and LTC, contribute to the acute rolling of PMNs on endothelial surface. Tumor necrosis factor (TNF), interleukin‐1 (IL‐1) and lipopolysaccharide activate endothelial cells to synthesize interleukin‐8 (IL‐8), a potent chemotactic and proadhesive mediator for PMNs, and further adhesion molecule (E‐selectin), a mediator of long‐term adhesion between PMN and endothelium. After adhesion and migration to the focus of inflammation, PMNs induce inflammation by aggregating, releasing hydrolyzing enzymes, generating lipid peroxidation products such as prostaglandins and LTB4, and oxygen derived free radicals. In studies on the pathogenesis of seronegative spondyloarthropathies, we have shown persistently aberrant PMN function evidenced by enhanced chemotaxis and high production of toxic oxygen derived free radicals by PMN. In the development of chronic inflammation, these aberrations may play a role. Lipopolysaccharide, shown to persist in such patients, could act as a priming factor. The triggering factor(s) and factors contributing to the chronic inflammation in rheumatoid arthritis are not known. In chronic diseases, synovial inflammation is characterized by monocyte/macrophage products such as IL‐1, TNF, interleukin‐6 (IL‐6), IL‐8, colony‐stimulating factors, lysosomal enzymes, PGE2, LTB4, and oxygen derived free radicals. However, in the acute phase or during flare‐up of chronic diseases, PMNs contribute to the inflammation by ingesting rheumatoid factors and immune complexes and by producing oxygen derived free radicals. During the first 1‐2 years of rheumatoid arthritis, a low response to chemotactic stimuli and low production of oxygen radicals by peripheral blood PMNs seem to be associated with benign disease and a lack of early destruction of joints measured by the presence of radiological erosions.
Biopharmaceutical Aspects of Tolfenamic Acid
Authors: Pedersen Søren Bols
Published: March 2009

Abstract The pharmacokinetics of tolfenamic acid is well described by a two‐compartment model with relatively short half‐lives (T/2 β 1‐2 hours) and tolfenamic acid is highly protein‐bound with small volumes of distribution. It is cleared relatively fast (150‐200 ml/min.), mainly by hepatic metabolism and the metabolites are renally cleared as glucuronic acid conjugates. The peroral absorption is good and the peroral bioavailability is about 75%, as first pass metabolism accounts for about 20%. Tolfenamic acid shows linear pharmacokinetics and during multiple dosage regimen, i.e. thrice daily, no accumulation beyond the second dose is observed. The bioavailability in dependence of age and disease has been studied and only in the case of severe liver or kidney impairment, a change in dosage regimen seems warranted. The development of different formulations will be outlined, mainly on rectal delivery, on sustained release and rapid release oral formulations, on topical ointment, and on parenteral delivery. The problems with tolfenamic acid in pharmaceutical formulation caused mainly by poor solubility will be discussed. Formulations ready for the market now or very soon are Clotam® capsules (tablets), Clotam® retard tablets, Clotam® suppositories, and Clotam® oral suspension, whereas rapid tablets, topical ointments, and parenteral formulations need further development to be ready for marketing in the years to come.
Migraine ‐ Diagnosis and Pathophysiology
Authors: Tfelt‐Hansen Peer
Published: March 2009

Abstract The new classification of headaches will be briefly described. The main primary headaches are migraine with and without aura, tension‐type headache and cluster headache. The operational diagnostic criteria for migraine with aura, migraine without aura and episodic tension‐type headache will be presented. After this the clinical pictures of migraine with aura (previously classic migraine) and migraine without aura (previously common migraine) will be described. At last the current concepts concerning pathophysiology, regional cerebral blood flow changes, changes in extra‐ and intracranial arteries and mechanisms of action of ergotamine and sumatriptan will be presented.
Tolfenamic Acid in Acute and Prophylactic Treatment of Migraine: A Review
Authors: Hansen Per Evald
Published: March 2009

Abstract The possible role of prostaglandins (PGs) in migraine has been the subject of increasing attention after the rather dramatic experiments done in man by Bergström and coworkers more than 25 years ago (1965). The role of PGs in migraine, however, is still hypothetical and not yet explained. PGs are known to sensitize nociceptors and produce hyperalgesia. PGs are involved in platelet aggregation thereby releasing serotonin. Vasodilatation, oedema and hyperalgesia in migraine have much in common with an inflammatory reaction. Tolfenamic acid (TA) inhibits PG biosynthesis and action and has an anti‐aggregatory effect. TA is better than aspirin and as effective as ergotamine in treatment of acute migraine attacks. TA has fewer side effects than ergotamine. TA is as effective as propranolol in prophylactic treatment of migraine. The dose regimen of TA in acute treatment of migraine is 200 mg when the first symptoms of migraine appear. The treatment can be repeated after 2‐3 hours if satisfactory effect is not obtained. The dose regimen of TA in prophylactic treatment of migraine is one sustained release tablet of 300 mg or 100 mg 3 times daily. After a treatment period of three months the regimen should be re‐evaluated.
The Vasodilatory Effects of Ketamine on Isolated Rabbit Portal Veins
Authors: Yamazaki Mitsuaki , Momose Yasunori , Shakunaga Kiyoshi , Kamitani Kazuo , Ito Yusuke
Published: March 2009

Abstract: The vasodilation mechanism induced by ketamine was investigated in isolated smooth muscle strips of rabbit portal veins. Ketamine inhibited both the phasic and tonic components of K+‐induced contraction at concentrations greater than 500 μM and 100 μM, respectively. This effect was reversible and concentration‐dependent with concentrations up to 1 mM. These effects were similar to those producd by verapamil. In the presence of 60 mM K+, application of Ca2+ (2.5 mM) in the perfusing solution caused tonic contraction of the smooth muscle, and ketamine at concentrations larger than 10 μM strongly inhibited this Ca2+‐induced contraction. Ketamine (100 μM) also inhibited the K+‐induced contractions significantly in the absence and presence of guanethidine, tetrodotoxin and propranolol. Ketamine produced similar concentration‐dependent relaxations in the tissues with and without endothelium. These results indicate that in rabbit portal vein, vasodilation produced by ketamine is not endothelium‐dependent but is likely to be due to blockade of the voltage‐gated influx of extracellular Ca2+.
Post‐Rest Potentiation and its Decay after Inotropic Interventions in Isolated Rat Heart Muscle
Authors: Ravens Ursula , Link Susanne , Gath Jennifer , Noble Mark I. M.
Published: March 2009

Abstract:The effects of various inotropic interventions on post‐rest potentiation and its decay were investigated in isolated cardiac muscle. The inotropic interventions studied were: reduced extracellular Na+ and elevated extracellular Ca2+concentration; exposure to ouabain, monensin, isoprenaline, phenylephrine and cirazoline. Force of contraction (stimulation frequency 2 Hz) was measured isometrically in left atria and right ventricular strips of rat hearts. Maximum post‐rest potentiation was reached after 10 sec. of rest and amounted to 245±26% of pre‐rest control in ventricle and 192±15% in atria. Ca2+‐recirculation fraction was calculated from the decay of post‐rest potentiation after resumption of regular stimulation, it was 0.77±0.01 in 11 control ventricular strips. High concentrations of caffeine (3 mmol/1) completely abolished post‐rest potentiation in both tissues. The development of post‐rest potentiation was accelerated in the presence of most of the inotropic agents. However, with the exception of ouabain and only in atrial muscle, none of the inotropic interventions produced higher post‐rest contraction amplitudes than during controls. In rat heart muscle, the inotropic interventions studied are not any more effective in augmenting force of contraction than prolonged stimulation intervals. This suggests that (1) the distribution of Ca2+into the sarcoplasmic reticulum is at a maximum during post‐rest potentiation; (2) modifications of signal transduction pathways cannot further increase post‐rest potentiation; and therefore that (3) shifts in Ca2+distribution act as a limiting factor.
Heterogenous Binding of3H‐Remoxipride to Membranes of Rat Liver and Brain
Authors: Ross Svante B.
Published: March 2009

Abstract:The binding of the antipsychotic agent3H‐remoxipride to membranes of rat liver and brain (whole brain and cerebellum) was studied with filtration technique. Saturable high affinity binding was obtained for all three types of tissue preparations. Heterogenous binding sites were found since various types of compounds inhibited the binding of3H‐remoxipride with shallow dose‐response curves. In the liver preparation it was possible to differentiate between two different binding sites. One site, called rem1, was defined with 100 nM alaproclate and bound σ2ligands with high affinity, e.g. haloperidol, GBR 12909, DTG and (+)‐3‐PPP. High correlation (r=0.93) was obtained between the inhibition of the binding of3H‐remoxipride to the rem1site and the inhibition of the binding of the σ ligand3H‐DTG reported previously (Ross 1991), indicating that the rem1site is identical to a σ2‐like binding site. The other3H‐remoxipride binding site in the rat liver, rem2, appears to be identical to the site binding alaproclate, proadifen and cocaine with high affinity. Cd2+and Zn2+were potent inhibitors of both binding sites, Cd2+particularly of rem2binding and Zn2+preferably of rem1binding. The apparent Bmax(pmol/g original tissue) and KD(nM) values for rem1binding were 441±43 and 80±14, and for rem2binding 727±116 and 95±6. The binding of3H‐remoxipride to the brain preparations was also inhibited with shallow dose‐response curves. The Bmaxvalues for the preparations of whole brain and cerebellum were 67±15 and 71±9 pmol/g original tissue, respectively and the KDvalues were 171±19 and 176±6 nM. The IC50of the compounds were highly correlated to the IC50values for the rem1binding in the liver (r=0.96) and to IC50values for the inhibition of3H‐DTG binding in rat brain reported previously (Ross 1991). Cd2+and Zn2+ions also inhibited the binding of3H‐remoxipride in the brain preparation but at higher concentrations compared with the liver preparations. The present results indicate that the main part of the binding in the brain preparations occurs to σ‐like recognition sites.
Four Weeks Inhalation Exposure to n‐Heptane Causes Loss of Auditory Sensitivity in Rats
Authors: Simonsen Leif , Lund Saren P.
Published: March 2009

Abstract: The effects of exposure to 800 or 4000 p.p.m. of n‐heptane, CAS No. [142‐82‐5]) 6 hr per day during a period of 28 days, on the function of the auditory system were examined by measurements of auditory brain stem response (ABR) in Long Evans rats. The ABR was measured simultaneously with both needle electrodes and implanted electrodes. The wave forms recorded with the two types of electrodes were similar, but the amplitudes were largest on the recordings with implanted electrodes. The overall ratio between the amplitudes obtained with implanted electrodes and with needle electrodes was 1.4 for peak la and 2.5 for peak IV of the ABR. The exposure to rc‐heptane (4000 p.p.m.) reduced the amplitudes of components la and IV of the ABR. The reduction was most consistent for component IV and most pronounced at higher frequencies and intensities. The reduction in ABR corresponds to an increase in the auditory threshold of approximately 10 dB at all frequencies. Neither the latencies nor the interpeak latencies of components la and IV were changed. No significant changes in ABR were observed in the group exposed to 800 p.p.m. The mechanism behind the ototoxicity of organic solvents is discussed.
Slight Renal Effect of Mercury from Amalgam Fillings
Authors: Eti Serife , Weisman Richard , Hoffman Robert , Reidenberg M. M.
Published: March 2009

Abstract: The current study was to answer the question: Is enough mercury absorbed from dental amalgam fillings to produce renal damage? One hundred healthy adults (18–44 years old) filled out health questionnaires and voided urine samples. Urine mercury concentration and N‐acetyl‐β‐glucosaminidase (NAG) were measured. Subjects were grouped into those having amalgam fillings (N=66) and those without (N=34). Median (95% Confidence Interval) urine mercury was 1 (1–2) and 0 (0–0.6) ng/ml (P<0.01) and median urine NAG was 23 (18–27) and 16 (11–18) units (P<0.05) in the two groups respectively. People with mercury amalgam fillings excreted slightly more mercury than people without them, and have a very small increase in urinary NAG excretion that is probably of no clinical significance. This dose of mercury absorbed from amalgam appears to be too little to be a public health hazard for renal injury.
Vascular versus Myocardial Selectivity of Dihydropyridine Calcium Antagonists as Studiedin Vivoandin Vitro
Authors: Nordlander Margareta , Abrahamsson Tommy , Åkerblom Birgitta , Thalén Pia
Published: March 2009

Abstract:The use ofin vitromodels for the study of cardiovascular effects of drugs may not be representative for thein vivotherapeutic effects. However, drug effectsin vivoare often difficult to assess because of counteracting reflexes and auto‐regulatory rearrangements. To solve this dilemma, the present study presents a two‐step method using bothin vivoandin vitrotechniques to investigate vascular versus myocardial selectivity of three dihydropyridine calcium antagonists: amlodipine, felodipine and nifedipine. The ratio between intravenous drug doses causing 25% reduction in mean arterial blood pressure (vascular potency) and in heart rate (cardiac chronotropic potency) was determined in anaesthetised spontaneously hypertensive rats during autonomic cardiac blockade. In isolated hearts from spontaneously hypertensive rats, the inotropic versus chronotropic potency ratio was determined between the two drug concentrations producing a 25% reduction in cardiac contractility (dP/dt max) and in heart rate, respectively. The vascular versus chronotropic selectivityin vivowas higher for felodipine (121) than for nifedipine (47) and amlodipine (15). The inotropic versus chronotropic potency ratios obtained from thein vitrostudies were: felodipine (1), amlodipine (2) and nifedipine (20). Thein vitroresults were used to extrapolate the vascular versus cardiac chronotropic selectivity obtainedin vivoto a vascular versus myocardial selectivity drug ratio, being 20 and 60 times higher for felodipine than for amlodipine and nifedipine, respectively.
The Phospholipid Drug Glyceryl‐phosphoryl‐O‐serine Modulates Pituitary Adrenocorticotropin and Hypothalamic Corticotropin Releasing Hormone in vitro Secretion in the Aging Rat
Authors: Chiarenza A. , Lempereur L. , Cantarella G. , Barbera N. , Maugeri M. , Scapagnini U. , Bernardini R.
Published: March 2009

Abstract: We have investigated the effects of the novel phospholipid′ yceryl‐phosphoryl‐O‐serine (GPS) on pituitary ACTH and hypothalamic corticotropin releasing hormone secreti ro in cultures from both 2‐ and 24 month‐old Sprague‐Dawley rats. Basal levels of ACTH in primary cultures o′ cells from 24 month‐old rats were lower than (100±12 pg/105 cells) in 2 month‐old rats (207±18 pg/105 cells). medium corticotropin releasing hormone levels in hypothalamic cultures were higher in 24 month‐old rats (45±7 pg/well/20 min.), than in 2 month‐old rats (29±5.5 pg/well/20 min.). Treatment of both pituitary cells with corticotropin releasing hormone and hypothalami with serotonin resulted respectively in a significant, concentration‐dependent, increase of medium ACTH and corticotropin releasing hormone. However, concentration‐response curves for ACTH and corticotropin releasing hormone were shifted to the right in cultures from 24 month‐old rats. Incubation with graded concentrations of GPS produced significant increase in medium ACTH and corticotropin releasing hormone in cultures from 24 month‐old rats, whereas the drug was ineffective in stimulating secretion of both hormones from 2 month‐old rat cells. In addition, the adenylate cyclase stimulator forskolin and the protein kinase C activator oleyl‐acyl‐glycerol stimulated ACTH secretion in pituicytes from rats of both ages. However, response to oleyl‐acyl‐glycerol was blunted in pituicytes from 24 month‐old rats. Combination of either forskolin or oleyl‐acyl‐glycerol with GPS resulted in a potentiation of the effect. Our data confirm an impairment of both pituitary ACTH and hypothalamic corticotropin releasing hormone secretion in the aging rat. Results suggest that defi‐citary signal transduction is possibly among causes of such impairment. Phospholipid drugs, such as GPS, appear to possess modulating effects on both pituitary ACTH and hypothalamic corticotropin releasing hormone.
Metabolism‐Dependent Toxicity of Methimazole in the Olfactory Nasal Mucosa
Authors: Brittebo Eva B.
Published: March 2009

Abstract:In mice given a single intraperitoneal injection of the antithyroid drug methimazole (0.44 mmol/kg; 50 mg/kg) detachment of the olfactory neuroepithelium and necrosis of the Bowman’glands in the lamina propria was observed 24 hr after administration. Three days after administration there was an atypical epithelium throughout the olfactory region and the Bowman's glands had disappeared. Pretreatment with the olfactory cytochrome P450 inhibitor metyrapone protected against the methimazole‐induced changes at this site. In mice injected with the methimazole analogues 1‐methylimi‐dazole or 4‐methylimidazole (0.44 mmol/kg; 36 mg/kg) or the antithyroid drug propylthiuracil (0.22 mmol/kg; 38 mg/kg) no morphological changes were observed in the olfactory mucosa. The results suggest that methimazole‐induced toxicity in the olfactory mucosa is related to metabolism‐dependent changes of the thiol group.
Adenosine, Adenosine Receptors and the Actions of Caffeine *
Authors: Fredholm Bertil B.
Published: March 2009

Abstract:Of the known biochemical actions of caffeine, only inhibition of adenosine receptors occurs at concentrations achieved during normal human consumption of the drug. Under normal physiological conditions, adenosine is present in sufficient concentrations to activate A1and A2areceptors. Via actions on A, receptors, adenosine decreases neuronal firing and the release of neurotransmitters. The exact mechanisms are not known, but several possibilities are discussed. Via actions on A2areceptors, adenosine ‐ and hence caffeine ‐ can influence dopaminergic neurotransmission. Caffeine can induce rapid changes in gene expression and, somewhat later, marked adaptive changes. These include antiepileptic and neuroprotective changes. Thus, caffeine has a number of central effects directly or indirectly related to adenosine receptors. Some of these are potentially useful, and drug development based on the actions of caffeine should be interesting.
Characterization of the Anticonflict Effect of MK‐801, a Non‐Competitive NMDA Antagonist
Authors: Söderpalm A. K. , Blomqvist O. , Engei J. A. , Söderpalm B.
Published: March 2009

Abstract:Brain serotonergic, noradrenergic and GABAergic mechanisms are all involved in the regulation of conflict behaviour, and the GABAA/benzodiazepine receptor complex may play the most central role in this context. Since facilitation of GABAergic inhibitory transmission produces anticonflict effects, it has been suggested that antagonism of excitatory inputs may serve the same cause, and, indeed, blockade of excitatory neurotransmission mediated via N‐methyl‐D‐aspartate (NMDA), receptors, produces anticonflict effects. In the present study, using a modified Vogel's rat conflict model, we have investigated whether the anticonflict effect of the non‐competitive NMDA antagonist MK‐801 can be linked to NMDA receptor blockade, and if stimulation of these receptors instead produces proconflict effects. The tentative involvement of noradrenergic, serotonergic or GABAergic effects in the MK‐801‐induced anticonflict effect was also studied. MK‐801 produced a dose‐dependent and specific anticonflict effect (maximal effect after 0.05 mg/kg, intraperitoneally,–90 min.). This anticonflict action was completely counteracted by NMDA in a dose (0.125 μg, intracerebroventricularly) not affecting behaviourper se. The highest dose tested of NMDA alone (0.5 μg) tended to produce a proconflict effect, but this action may be unspecific due to concomitant drug‐induced motor‐inhibition. Neither bicuculline and picrotoxin, antagonists at the GABAA/benzodiazepine receptor complex, nor the adrenoceptor antagonists propranolol and prazosin significantly altered the MK‐801‐induced anticonflict effect, whereas L‐5‐HTP (50 mg/kg, intraperitoneally, after inhibition of peripheral decarboxylation with benzerazide) completely abolished the anticonflict effect of MK‐801. The results indicate that the anticonflict effect of MK‐801 is primarily mediated by antagonism of NMDA receptors, and that brain 5‐HT systems may also be involved in this effect.
Antagonism of Reserpine‐Induced Suppression of Spontaneous Motor Activity by Stimulation of 5‐HT1AReceptors in Rats
Authors: Ahlenius Sven , Salmi Peter
Published: March 2009

Abstract:The 5‐HT1Aand the DA D2receptor agonists 8‐OH‐DPAT (0.05–3.2 mg kg–1subcutaneously, –20 min.) and quinpirole (0.08–1.25 mg kg–1subcutaneously, –20 min.), respectively, both partially antagonized reserpine‐induced (5 mg kg–1subcutaneously, –16 hr) suppression of spontaneous motor activity in the rat. Four different aspects of the spontaneous motor activity were recorded in a photocell‐equipped open‐field (8x8 photocells, 90 mm apart, defining two horizontal planes):locomotor activity(all photocell counts at the lower level);rearing(all photocell counts at the upper level);forward locomotion(the proportion movements across the arena);peripheral activity(the proportion locomotor activity as picked up by the photocell beam closest to the wall, i.e. 25 mm). As denned by these variables, the pattern of activity produced by 8‐OH‐DPAT or quinpirole were indistinguishable, The effects produced by 8‐OH‐DPAT were fully antagonized by the 5‐HT1antagonist (–) pindolol (4 mg kg–1subcutaneously, –30 min.), but not by the DA D2receptor antagonist raclopride (2 mg kg–1subcutaneously, –30 min.) nor by the 5‐HT2receptor antagonist ritanserin (2 mg kg–1subcutaneously, –30 min.), whereas effects produced by quinpirole were fully antagonized by raclopride (2 mg kg–1subcutaneously, –30 min.). Effects produced by quinpirole, but not 8‐OH‐DPAT, were potentiated by administration of the DA D1agonist SKF‐38,393 (3 mg kg–1subcutaneously, –20 min.). It is concluded that effects by 8‐OH‐DPAT on spontaneous motor activity in the reserpine treated rat primarily are due to stimulation of postsynaptic 5‐HT1Areceptors.
Nicotine Dependence, Midbrain Dopamine Systems and Psychiatric Disorders
Authors: Nisell Magnus , Nomikos George G. , Svensson Torgny H.
Published: March 2009

Abstract:Compelling evidence exists that tobacco‐smoking represents a form of drug addiction to nicotine. Like several drugs of abuse, nicotine activates the mesolimbic dopamine system and this effect appears to be of critical importance for the reinforcing properties of the drug. Specifically, nicotine has been shown to increase burst activity in dopamine neurones of the ventral tegmental area, i.e. a mode of firing pattern in these cells which is physiologically associated with basic motivational processes underlying learning and cognitive behaviour. The stimulatory action of nicotine on mesolimbic dopamine neurones is exerted both at the somatodendritic and at the terminal levels. Yet, the release of dopamine in the nucleus accumbens induced by systemically administered nicotine is abolished by the nicotinic receptor antagonist, mecamylamine when administered locally in the ventral tegmental area, but not in the nucleus accumbens. Whereas continuous infusion of nicotine into the ventral tegmental area produces a long‐lasting increase in accumbal dopamine release, analogously to the effect of systemically administered nicotine, continuous infusion of nicotine into the nucleus accumbens produces a very short‐lasting dopamine release. Thus, nicotinic receptors in the ventral tegmental area appear to be more significant than those located in the nucleus accumbens for mediating the stimulatory effect of nicotine on dopamine release in the nucleus accumbens. The effect of nicotine on midbrain dopamine systems may help to explain the extremely high prevalence of tobacco‐smoking in schizophrenics, who frequently display so‐called hypofrontality, i.e. a reduced functional activity in the prefrontal cortex which provides a direct input to the ventral tegmental area dopamine cells. Specifically, the prefrontal cortex seems to control phasic activity, i.e. essentially burst firing, but not tonic activity in these neurones through glutamatergic pathways. Accordingly, impaired functional activity in the prefrontal cortex in the rat has been found to decrease burst firing in ventral tegmental dopamine cells, an effect which can be antagonized by nicotine pretreatment. Moreover, chronic, but not acute nicotine administration has been found to increase dopamine metabolism in the prefrontal cortex. Thus, the intense nicotine intake in psychotic individuals may, in effect, reflect an attempted self‐medication. The finding that cigarette‐smoking can help to normalize the impaired sensory gating in schizophrenic patients provides additional evidence for this notion. In summary, the physiological pattern of activation of dopamine neurones induced by nicotine may be particularly well suited for its ability to induce psychological dependence as well as to partly reverse a probably distorted dopamine signalling in psychotic individuals.
Dexamethasone Inversely Regulates DNA Synthesis and Phosphoenolpyruvate Carboxykinase mRNA Levels in Cultured Rat Hepatocytes: Interactions with Insulin, Glucagon, and Transforming Growth Factor β1.
Authors: Thoresen G. Hege , Refsnes Magne , Dajani Olav F. , Johansen Ellen J. , Christoffersen Thoralf
Published: March 2009

Abstract: In hepatocytes, glucocorticoids control the expression of several genes and exert significant, but complex, regulation of the proliferation. To shed more light on the growth responses to glucocorticoids in these cells, we treated adult rat hepatocytes in primary culture with dexamethasone, in various combinations with other hormones (insulin, glucagon, transforming growth factor β1 (TGFβ1)), and examined the relationship between the effects on the DNA synthesis and the mRNA level of phosphoenolpyruvate carboxykinase, a gene typically expressed in differentiated hepatocytes. Insulin exhibited the previously observed suppressing effect on the glucocorticoid‐induced phosphoenolpyruvate carboxykinase mRNA level, and also reversed growth‐inhibitory effects of the glucocorticoid. Dexamethasone and glucagon (via cAMP) acted strongly synergistically both in enhancing the phosphoenolpyruvate carboxykinase expression and inhibiting the growth, the inhibitory effect of glucagon on DNA synthesis being totally dependent on dexamethasone. The effects of dexamethasone plus glucagon on both the phosphoenolpyruvate carboxykinase mRNA abundance and the DNA synthesis were partially counteracted by insulin. Dexamethasone is permissive for a promoting effect of TGFβ1 on phosphoenolpyruvate carboxykinase expression, and was found to increase the maximal inhibitory effect of (but reduced the sensitivity to) TGFβ1 on the DNA synthesis. The results indicate that there is an inverse glucocorticoid‐induced regulation of the DNA synthesis and the expression of a liver‐typical gene.
Concomitant Single‐Dose and Multiple‐Dose Pharmacokinetics of Terodiline in Man, with a Note on its Enantiomers and Major Metabolites
Authors: Hallén Bengt , Gabrielsson Johan , Nyambati Samuel , Johansson Agneta , Larsson Eva , Guilbaud Olivier
Published: March 2009

Abstract:Single‐dose and multiple‐dose pharmacokinetics of terodiline were studied in 20 healthy volunteers by giving an initial oral dose of deuterium‐labelled terodiline (12.5 mg or 25 mg) followed by multiple doses of Mictrol tablets (12.5 mg b.i.d. for 14 days and 25 mg b.i.d. for 14 days orvice versa). The enantiomer serum concentration ratio of S(–)/R(+) terodiline was close to unity at steady‐state as well as during the disposition phase. The average single‐dose kinetic parameters for the racemate after the 12.5 mg dose were: maximum serum concentration 41 μg/1, the corresponding time 3.4 hr, terminal half‐life 61 hr, oral clearance 77 ml/min., renal clearance 12 ml/min. and apparent volume of distribution 382 1. The single‐dose kinetics for the 25 mg dose and the multiple‐dose kinetic parameters showed that linear kinetics prevailed. The average steady‐state serum concentration was 275 μg/1 at the lower dose and 509 ug/1 at the higher dose. The degree of fluctuation during a dosage interval was 19% and the time to steady‐state was about 9 days. The fraction unbound was about 8%. Unconjugated p‐hydroxylated terodiline, p‐hydroxy‐m‐methoxyterodiline and hydroxy‐tert‐butyl‐terodiline constituted 15%,<1% and 5%, respectively, of the terodiline steady‐state levels.
Distribution of all‐trans‐, 13–cis‐ and 9‐;cis;‐Retinoic Acid to Whole Rat Embryos and Maternal Serum Following Oral Administration of a Teratogenic Dose of all‐;trans‐Retinoic Acid
Authors: Ward Simon J. , Morriss‐Kay Gillian M.
Published: March 2009

Abstract: Maternal administration of 200 mg/kg all‐trans‐retinoic acid to rat embryos at early limb stages of development (day 12 to day 13.5 post coitum) results in limb reduction defects. In order to determine the duration of exposure of the embryo to raised levels of all‐trans‐retinoic acid, we have used high performance liquid chromatography to measure retinoid levels at a series of time intervals following maternal administration on day 12.5 post coitum. Raised levels of all‐trans‐retinoic acid and 13‐cis‐retinoic acid were detectable in embryos after 30 min., reached a peak at 2 hr, and had fallen sharply by 4 hr. 13‐cis‐Retinoic acid levels were undetectable after 4 hr, and all‐trans‐retinoic acid levels after 8 hr. 9‐cis‐retinoic acid levels rose more slowly, were less elevated, and fell more gradually than the other two retinoids. The retinoid profiles in maternal serum were similar. The results indicate that induction of limb abnormalities by all‐trans‐retinoic acid in rat embryos is associated with a relatively short‐term rise in embryonic retinoid levels.
Renal Toxicity after Oral Administration of Lead Acetate during Pre‐ and Post‐Implantation Periods: Effects on Trace Metal Composition, Metallo‐Enzymes and Glutathione
Authors: Gupta G. S. , Singh Jarnail , Parkash P.
Published: March 2009

Abstract:The present study was undertaken to compare the effects of 10–50 mg/kg b.wt. of Pb acetate after chronic treatment through oral gavage on: (a) the distribution of trace elements such as Fe, Cu, Zn, and Mn, (b) enzyme activity of δ‐amino levulinic acid dehydratase (δ‐ALAD) and alkaline phosphatase, and (c) glutathione (GSH) in kidney and (d) δ‐ALAD in blood of pregnant and non‐pregnant mice. Treatment with Pb acetate was given on every alternate day for 4 weeks prior to mating and for 3–4 weeks until pregnancy became apparent and confirmed by laporatomy. Lead administration reduced the rate of reproduction as assessed by number of living viable embryos. During normal pregnancy renal Cu, Fe and GSH tended to decline although non‐significantly and continued to do so after lead administration. Mn was considerably and significantly elevated, whereas activity of δ–ALAD (non‐activated) was quite low in pregnant mice. Following administration of Pb acetate, kidneys of pregnant and non‐pregnant dams accumulated Pb in a dose‐dependent manner, but as compared to non‐pregnant mice, Pb increase in pregnant dams was significantly lower. Pb toxicity was associated with the loss of δ‐ALAD in blood and kidney, but unlike the non‐activated form of δ‐ALAD, the dithiothreitol‐activated form of δ‐ALAD declined in a significant amount. The residual activity showed a high degree of negative correlation with endogenous Pb as well as with Zn/Pb ratio. Pb toxicity did not modify renal Fe, Cu and Zn in the nonpregnant state, but reduced renal Fe during pregnancy. On the other hand, Mn decline is a sensitive indicator of Pb toxicity and correlated with the Pb content during pregnancy. While the increase in renal alkaline phosphatase activity in pregnancy persisted even after Pb administration up to 25 mg/kg b.wt. Pb acetate, the activity of alkaline phosphatase in non‐pregnant mice did not change after lead treatment. The level of alkaline phosphatase did not correlate with the Zn content but correlated with endogenous levels of Pb, Mn or Zn/Mn ratio. Increase in GSH during the pregnant and nonpregnant state after Pb exposure was apparent. It appears that the body attempts to regulate the Pb toxicity by promoting self‐defence by enhanced production of thiol compounds such as glutathione. It is concluded that pregnancy modifies renal lead retention and lead toxicity in terms of trace metal composition and some metalloenzymes.
The Effect of a Benzalkonium Chloride‐Containing Nasal Spray on Human Respiratory Mucosa in vitro as a Function of Concentration and Time of Action
Authors: Berg Øystein H. , Henriksen R. N. , Steinsvåg S. K.
Published: March 2009

Abstract: Human respiratory mucosa was exposed to oxymetazoline nasal spray in varying concentrations and for varying periods of time in vitro. The drug destroyed the tissue in a concentration‐ and time‐dependent manner. In the experiments with various concentrations of the spray, some tissue fragments retained their viability throughout the experiment. This number increased parallel to a decrease in concentrations of the test substance. All the tissue fragments exposed to undiluted nose spray underwent severe destructive alterations during the exposure period. These alterations appeared first and were most extensive in those exposed for the longest periods of time. It has previously been demonstrated that the toxic effect of oxymetazoline nasal spray in vitro is probably due to the preservative benzalkonium chloride. The apparent lack of consistency between the toxic effects of benzalkonium chloride in vitro and in vivo is discussed, with special reference to protective systems absent in vitro but present in vivo.
Defective Blood Coagulation is not Causative of Hepatic Haemorrhage Induced by Microcystin‐LR
Authors: Takahashi O. , Oishi S. , Watanabe M. F.
Published: March 2009

Abstract:Male rats were intraperitoneally administered a lethal dose of microcystin‐LR (a toxin of cyanobacteria). Prior to haemorrhage in the liver, blood coagulation and platelet aggregation activities were measured. The number of cellular components, white blood cells, red blood cells and, especially, platelets, decreased 1–1.5 hr after the injection. Plasma kaolin‐activated partial thromboplastin time was prolonged and fibrinogen concentration was reduced, but antithrombin III activity and fibrin degradation product concentration were not significantly changed. Platelet aggregation was not affected for up to 0.5–1.0 hr after administration. Sequential analyses of those parameters and hepatotoxic markers indicate that those hematologic changes as well as the hepatic injury occur suddenly after the massive bleeding. These results suggest that microcystin‐LR does not directly act on the haemostatic system to cause a disseminated intravascular coagulation‐like state. The decrease in blood coagulation activity and platelet particle concentration may be the results of secondary consumptive effects following the hepatic haemorrhage.
Interaction between Erythromycin and Nitrazepam in Healthy Volunteers
Authors: Luurila Harri , Olkkola Klaus T. , Neuvonen Pertti J.
Published: March 2009

Abstract: Interaction between erythromycin, a strong inhibitor of CYP3A4, and nitrazepam, a long‐acting benzodiazepine, was investigated in a double‐blind and randomized cross‐over study of two phases. Ten healthy volunteers received erythromycin (500 mgx3) orally or placebo for 6 days. On the fourth day they were given a challenge dose of 5 mg nitrazepam. Plasma samples were collected and psychomotor effects were measured during 42 hr after intake of nitrazepam. There was a statistically significant pharmacokinetic interaction between erythromycin and nitrazepam. Erythromycin increased the area under the nitrazepam concentration‐time curve by 25% (P<0.05) and the peak concentration by 30% (P<0.05). The concentration peak time of nitrazepam was shortened by over 50% (P<0.05). The elimination half‐lives did not change. Accordingly, as far as the metabolism of nitrazepam is concerned, erythromycin does not cause any major changes in the metabolism of nitrazepam. In psychomotor performance only minor differences were seen. It is concluded that the interaction between erythromycin and nitrazepam is of little clinical significance.
Lack of Haematological Effect of Oral Vanadium Treatment in Rats
Authors: Dai S. , Vera E. , McNeill J. H.
Published: March 2009

Abstract: Haematological effects of oral administration of ammonium metavanadate 0.19 mmol V/kg/day, vanadyl sulphate 0.15 mmol V/kg/day, and bis(maltolato)oxovanadium (IV) 0.18 mmol V/kg/day in drinking water for 12 weeks were investigated in Wistar rats. Some selected haematological indices of the peripheral blood, including haematocrit, haemoglobin, erythrocyte count, reticulocyte percentage, leukocyte count and its differential count, platelet count, and osmotic fragility of the erythrocyte were determined using the standard methods. It was found that, throughout the 12‐week experimental period, there were no significant differences between the untreated controls and various groups of vanadium‐treated rats in all of the parameters measured. It is thus concluded that ammonium metavanadate, vanadyl sulphate, and bis(maltolato) oxovanadium (IV), at least at the doses and at the duration of treatment employed, do not produce significant haematological toxicity in rats.
On the occasion of the 40th anniversary of Acta pharmacologica et toxicologica, May 5th, 1985
Authors: Bain James A.
Published: March 2009

Abstract: The first issue of Acta pharmacologica et toxicologica was circulated on May 5th, 1945, the very day on which World War II ended in Denmark. The journal is the official publication medium of the Scandinavian Pharmacological Societies. The societies are also represented by associate editors in the editorial board of Pharmacological Reviews. On the happy occasion of the anniversary, we were pleased to receive the following congratulation address from the editor of Pharmacological Reviews, James A. Bain, Ph.D., past president of the International Union of Pharmacology, and Professor of Pharmacology, School of Medicine Emory University, Atlanta, Georgia 30322, U.S.A.
Human Dioxin Receptor Chimera Transactivation in a Yeast Model System and Studies on Receptor Agonists and Antagonists
Authors: Rowlands J. Craig , Gustafsson Jan‐Åke
Published: March 2009

Abstract:A yeast dioxin receptor chimera model has been developed to study ligand binding and transactivation properties of the human dioxin receptor. Using this new yeast model, the human dioxin receptor chimera was found to possess a constitutive transactivity on aLacZreporter gene, however, the transactivation by the chimera was enhanced by the addition of several polycyclic aromatic hydrocarbons to the culture medium. The order of best polycyclic aromatic hydrocarbon inducer to worst correlated well with the knownin vitrodioxin receptor binding affinities for these polycyclic aromatic hydrocarbons. 7, 8‐Benzoflavone, a weak dioxin receptor agonist and strong antagonist of the mammalian dioxin receptor also behaved as a weak agonist and strong antagonist of the human dioxin receptor chimera expressed in yeast. The implications for these findings as well as the utility of this new yeast human dioxin receptor chimera model are discussed.