bluuebunny/crossref_metadata_2025 huggingface dataset:
Relative Dopamine D1and D2Receptor Affinity and Efficacy Determine Whether Dopamine Agonists Induce Hyperactivity or Oral Stereotypy in Rats
Authors: Arnt Jørn , Bøgeso K. P. , Hyttel John , Meier Eddi
Published: March 2009

Abstract:The effects of a range of dopamine (DA) agonists on stereotyped behaviour in rats were analysed and compared both with the affinity of the compounds for D1and D2receptor binding sitesin vitroand their ability to stimulate the adenylate cyclase activity in rat striatal homogenates. Full and partial agonists at the D1receptor coupled toadenylate cyclase do not induce stereotypies when given alone, whereas full D2agonists (e.g. quinpirole) induce hyperactivity but not oral stereotypies. Partial D2agonists (e.g. (—)‐3‐PPP) only induce sedation. Mixed D1/D2agonists (e.g. apomorphine) induce both hyperactivity and oral stereotypies. Maximum stereotypies were induced by combination of SK & F 38393 and a series of D2agonists, including full agonists and the partial D2agonist B‐HT 920, whereas partial agonists with low intrinsic activity (e.g. (‐)‐3‐PPP, EMD 23448) did not induce stereotypies when given together with SK & F 38393. However, these partial agonists reduced the maximum effect of apomorphine, whereas the full agonists (e.g. quinpirole, (—)‐NPA) and B‐HT 920 had no apomorphine antagonistic activity. The mixed D1/D2agonists apomorphine and N,N‐dipropyl‐5,6‐ADTN were only weakly influenced by SK & F 38393, or not at all. D1agonists with central effects, including SK & F 38393, SK & F 81297 (with relatively high efficacies), and the partial agonist SK & F 75670 with low efficacy, changed the hyperactivity induced by quinpirole into maximum oral stereotypy, whereas the peripheral D1agonist fenoldopam had no such effect. Inhibition of DA and NA synthesis with α‐methyl‐p‐tyrosine depleted striatal DA levels by 72 per cent and antagonized the hyperactivity induced by the D2agonists quinpirole and (—)‐NPA, but not that of apomorphine. Combination of SK & F 38393 and quinpirole induced maximum stereotypy in DA‐depleted animals. These results suggest that D1receptor tonus is a necessary prerequisite for the expression of a DA agonist's effect. The hyperactivity induced by full D2agonists appears to be mediated by D1tonus provided by endogenous DA activity, but stronger D1stimulation is necessary to induce oral stereotypy. A high degree of D1receptor activation increases the ability of partial D2agonists to induce hyperactivity or oral stereotypies since treatment with both SK & F 38393 and B‐HT 920 had marked effects while B‐HT 920 was ineffective. The behavioural stimulation induced by a particular DA agonist thus depends on relative D1/D2receptor affinity and also on the intrinsic activity at D2receptors, while intrinsic activity at D1receptors appears to be less important. The relative importance of D1and D2receptors for expression of different stereotypy patterns is useful forin vivoevaluation of the selectivity ratios of DA agonists.
Structure/Activity Relationships of a Homologous Series of Surfactants (Nonyl‐phenoxypolyethoxyethanols) on Rat Vaginal Bioelectric Activity over the Oestrous Cycle
Authors: Levin R. J.
Published: March 2009

Abstract: The spermicide nonoxynol‐9 is a member of a homologous series of alkylphenol‐ethoxylates (polyethoxyethanols) of general formula C9H19‐C6H6‐O‐(CH2CH2O)n‐1 CH2CH2OH. Nonoxynol‐9 when instilled into the vagina of anaesthetized rats causes a rapid fall in the transvaginal potential difference (p.d.). Using the time taken for the p.d. to fall to half its value (t1/2), the structure/activity relationship of a number of isosmolar solutions of the compounds on the vaginal p.d. was assessed during the oestrous cycle. Members of the series tested had n = 1.5, 4, 6, 8/9, 9, 10/11, 15, 20, 30 and 40 and were commercially available (Antarox CO series, GAF). At pro‐oestrus all compounds were ineffective. At metoestrus and oestrus the relationship between the activity of the series and the n value was clearly U‐shaped, a similar pattern was apparent at dioestrus. When n=40, 30 or 20 little or no effect was observed on the p.d. but the depressive activity was significant at n= 15 and became maximal at n=8/9 and 9. When n=6 the activity began to attenuate while at n = 4 and 1.5 it became very reduced. The relation between the ability to depress the p.d. and the moles of ethylene oxide (n) appeared to be related to the hydrophilic/hydrophobic balance of the compound. When n was > 15 the compounds were too hydrophilic to enter the membrane phase and cause disruption while when n < 6 they were too hydrophobic and had too small a molar volume to affect membrane function. The most potent structures around n = 8, 9 appear to be those employed as spermicides. The structure/activity data are of interest in relation to the use of non‐ionic detergents as enhancers of vaginal absorption and in highlighting the importance of the phase of the oestrous cycle employed for the testing.
Nephrotoxicity of Selectively Deuterated and Methylated Analogues of Tris‐BP and Bis‐BP in the Rat
Authors: Sederlund Erik J. , Omichinski James G. , Dahl Jon E. , Nelson Sidney D. , Dybing Erik
Published: March 2009

Abstract:Selectively deuterated and methylated analogues of the flame retardant tris(2,3‐dibromopropyl)phosphate (Tris‐BP) and its nephrotoxic metabolite bis(2,3‐dibromopropyl)phosphate (Bis‐BP) were compared to Tris‐BP and Bis‐BP in inducing acute renal damage in rats. None of the deuterated Tris‐BP or Bis‐BP analogues significantly altered morphological evidence of nephrotoxicity compared to the protio compounds. On the other hand, some of the selectively methylated analogues were much less nephrotoxic. Although the C1‐methyl analogues of both Tris‐BP and Bis‐BP were as potent nephrotoxicants as Tris‐BP and Bis‐BP, respectively, neither the C2‐methyl nor the C3‐methyl analogues were significantly nephrotoxic. Interestingly, whereas the 3,4‐dibromobutyl homologue of Tris‐BP was not nephrotoxic, the corresponding 3,4‐dibromobutyl‐Bis homologue was as nephrotoxic as Bis‐BP. Additional investigations with treatments that are known to decrease nephrotoxicity caused by several halogenated alkenes, showed that L‐(αS,5S)‐α‐amino‐3‐chloro‐4,5‐dihydro‐5‐isoxazoleacetic acid (AT‐125) and aminooxyacetic acid were without effects on Tris‐BP induced renal damage. Probenecid pretreatment led to a reduction in Tris‐BP and Bis‐BP tubular necrosis, these effects may be related to inhibition of Bis‐BP uptake in the kidney. It appears that the cysteine conjugate β‐lyase pathway is not involved in the generation of nephrotoxic metabolites of Tris‐BP.
Effect of μ‐ and ‐Opioid Agonists on the Electroconvulsive Seizure Threshold in Mice and Antagonism by Naloxone and MR 2266
Authors: Frey Hans‐Hasso
Published: March 2009

Abstract:The effects of μ‐agonists (morphine, fentanyl) andx‐agonists (U‐50,488, U‐69,593, bremazocine, nalbuphine, tifluadom) on the electroconvulsive threshold were studied in mice. The threshold could be significantly elevated by all drugs tested in a dose range that was in the order of magnitude of the antinociceptive ED50. Mice tolerant to the antielectroshock effect of morphine still reacted to U‐69,593. The antagonism of the anticonvulsant effect by the μ‐antagonist naloxone and thex‐antagonist MR 2266 was receptor‐specific only with fentanyl and U‐50,488. The other opioid agonists were either antagonized by both drugs (morphine, U‐69,593, bremazocine, nalbuphine) or even by the opposite antagonist (tifluadom). A synergistic effect of μ‐ andx‐stimulation is assumed for the mediation of the antielectroshock effect of opioid drugs, but drugs with high affinity and intrinsic activity at one receptor type (fentanyl, U‐50,488) are obviously able to bring about their antielectroshock effect through the one respective opioid binding site.
Pharmacokinetics of Etretin and Etretinate during Long‐Term Treatment of Psoriasis Patients
Authors: Larsen Frederik Grønhøj , Jakobsen Preben , Larsen Christian Gronhej , Kragballe Knud , Nielsen‐Kudsk Folmer
Published: March 2009

Abstract: The aromatic retinoic acid derivative etretin has recently been introduced in the treatment of severe psoriasis and other dyskeratoses. Hitherto, the use of the carboxylic acid ester analogue, etretinate, has been hampered by an extremely long elimination half‐life of up to 120 days for this drug. Seven patients of either sex from whom we recently reported single‐dose pharmacokinetics have been studied after 1 and 3 months multiple dose administration of the drugs. Four were given etretin and three etretinate. Etretin, both as drug and as metabolite, was absorbed faster than etretinate as judged from t‐lag, tm and t1/2ka. Etretin as drug was eliminated faster than the metabolite etretin, t1/2β 2.39 ± 1.16 days compared to 6.51 ± 2.06 days. In patients receiving etretinate the terminal disposition or elimination half‐lives for cis‐etretin (t1/2γ3 15.9 ± 9.9 days) were longer than for the metabolite etretin and exhibit a pronounced interindividual variation from 4.5 to 22.8 days. Similarly, cis‐etretin accumulated very marked in comparison to the metabolite etretin of the drug etretinate. Assuming 40% systemic availability for both drugs, the central compartment of distribution constituted about 12–32. in case of etretin and about 0.8‐3.6% in case of etretinate of the calculated apparent total volume of distribution at steady state, which showed mean values of 3.5 and 39.6 1‐kg.‐1, respectively, presumably reflecting the higher lipophilic nature of the latter compound.
Effects of Ouabain on86Rb‐Uptake,3H‐5‐HT‐Uptake and Aggregation by 5‐HT and ADP in Human Platelets
Authors: Andersson Tomas L. G. , Vinge Ellen
Published: March 2009

Abstract:In the search of sensitive models for actions of digitalis‐like substances on intact cells or tissues, the effects of ouabain on human platelets were investigated. In a concentration‐dependent manner ouabain 10‐8—10‐4M inhibited Na+‐K+‐ATPase activity measured as uptake of86Rubidium (86Rb), with about 90% inhibition of the total uptake at ouabain ≥ 10‐6M. An almost identical concentration‐effect curve was found for platelet uptake of3H‐serotonin (3H‐5‐HT). The platelet shape change reaction to exogenous 5‐HT (1 × 10‐6M) was suppressed by ouabain (10‐8‐10‐4M) in a concentration‐dependent manner, but with no clear maximum effect within the range tested. Aggregation induced by adenosine‐di‐phosphate (ADP 2 × 10‐6M) was enhanced by ouabain 10‐8‐10‐6M. At the highest concentration tested the rate of aggregation was increased by 31 % and the change in light transmission by 54%. At low concentrations (< 10‐8M) of ouabain, there was a tendency towards increased aggregation as well as increased uptake of86Rb, which may be a parallel to observations of positive inotropic effects of low concentration of glycosides, which do not inhibit Na+‐K+‐ATPase. The results show that human platelets can be used as a model tissue for studying effects of cardiac glycosides. This suggests that it may be useful for further investigations of the biological effects of agents with a similar effect profile, e.g. endogenous digitalis‐like substances.
Electrophysiological Effects of Amperozide in Papillary Muscles from Ferrets, Guinea‐Pigs and Rabbits
Authors: Arlock Per
Published: March 2009

Abstract:Amperozide, a novel psychotropic agent, in concentrations lower than 10 μM caused a homogenous prolongation only of the action potential in both guinea‐pig and rabbit papillary muscle. In concentrations ≥ 10 μM, amperozide caused a flattening of the action potential plateau and the later part of the repolarization phase became slower (longer), probably reflecting an impaired repolarizing Na‐Ca exchange current. The overshoot (OS) and the rate of rise of the action potential (dV/dtmax) were depressed. It is concluded that amperozide has a blocking action on the transmembrane calcium current since Isi(second inward current), DIA (depolarization induced automaticity) and the peak force of contraction were depressed. The blocking of the Isiwas use‐dependent resembling the actions of calcium‐antagonists like verapamil, except that it was less potent at equimolar concentrations. Amperozide in concentrations where it acted as an Isi‐blocker (above 10 μM), had depressing effects only on ouabain‐induced oscillatory events. No major differences in the effects of amperozide were apparent between guinea‐pig, ferret or rabbit papillary muscles.
Effects of Enprofylline, Theophylline and Terbutaline on Second Inward Currents in Papillary Muscles from Ferrets and Guinea‐Pigs
Authors: Arlock Per
Published: March 2009

Abstract:In ferret and guinea pig papillary muscles enprofylline (10 μM‐10 mM) and theophylline (0.1‐2 mM) alone or in combination with terbutaline (0.05 μM‐0.1 μM) decreased the action potential duration and increased the plateau height, increased the peak force of contraction and facilitated the depolarization‐induced automaticity. In voltage clamp, the xanthines alone or in combination with terbutaline increased second inward currents, ICa,fand ICa,2, but had relatively less effect on the time‐dependent outward current. No qualitative differences between enprofylline and theophylline could be detected but the former was about 5 times more potent in increasing ICa,f.In clinically relevant concentrations, enprofylline and theophylline alone, or in combination with terbutaline caused a small (2‐5%) shortening of the action potential.
Elevated Level of β‐Adrenoceptors in Intact Hepatocytes from Partially Hepatectomized Rats
Authors: Sandnes Dagny , Sager Georg , Sand Tor‐Erik , Refsnes Magne , Jacobsen Sten
Published: March 2009

Abstract: The binding characteristics of 125I‐iodocyanopindolol (125I‐ICYP) and 3H‐CGP‐12177 to intact hepatocytes and a particulate fraction prepared from hepatocytes from sham‐operated and partially hepatectomized rats were compared. In the paticulate fraction, the β‐adrenoceptor number increased 4‐10‐fold after partial hepatectomy. 125I‐ICYP binding to intact cells demonstrated a high fraction of non‐specific binding, although phentolamine was included in the assay to reduce non‐specific binding. 3H‐CGP‐12177 binding to intact cells also demonstrated a higher fraction of non‐specific binding than in most cell types. In intact cells, the β‐adrenoceptor number increased 5‐6‐fold after partial hepatectomy. The number of receptors was comparable in intact cells and the broken cell preparation, indicating that receptors are conserved during the preparation of the particulate fraction.
The Bioavailability of Rectally Administered Morphine
Authors: Jonsson Torsten , Christensen Christian Broen , Jordening Henrik , Frølund Carsten
Published: March 2009

Abstract:Plasma concentrations of morphine were followed for 24 hours in eight patients after intravenous and rectal administration of 10 mg morphine chloride. The plasma levels of morphine were determined by a sensitive and specific radioimmunoassay based upon an extraction procedure which separates morphine from its major polar metabolites. The bioavailability of morphine after rectal administration was found to be 53.3 ± 17.8% (mean ± S.D.). Peak concentrations of 16.3 ± 8.7 ng ml‐1were reached after 59 ± 16 min. The study indicates that first pass elimination of morphine may be partially avoided by rectal administration.
Insulin Clearance from Plasma in Type I (Insulin‐Dependent) Diabetic Patients: Influence of Glycaemic Level
Authors: Thorsteinsson Birger , Fugleberg Steen , Binder Christian
Published: March 2009

Abstract: The influence of the actual glycaemic level on the kinetics of insulin disappearance from plasma was studied in 16 type I diabetic patients. Constant intravenous infusion of insulin (1‐5 mU · kg‐1 · min.‐1) was used to achieve different levels of steady state plasma free insulin concentrations, while the blood glucose level was clamped at normoglyc‐aemia, 4.1 ± 0.1 mmol/1 (mean ± S.E.M.), and mild hyperglycaemia, 8.2 ± 0.1 mmol/1. The experimentally determined data were compared using a previously validated model of first order kinetics for insulin disappearance from plasma in diabetic patients. At the physiological insulin concentration range the median clearance rate of insulin was 23 ml · kg‐1 · min.‐1 (range 16‐26) at normoglycaemia and 23 ml · kg‐1 min.‐1 (19‐35) at hyperglycaemia (P = 0.45). At supraphysiological levels, insulin was cleared at a lower rate at normoglycaemia than at hyperglycaemia. No correlation was observed between the insulin clearance rate and the duration of diabetes or the haemoglobin A1c level (both Spearman's rho = 0.08). In conclusion, the insulin clearance rate from plasma is independent of the actual glycaemic level and hardly influenced by the long‐term glycaemic level in type I diabetic patients.
Decrease in the Number of Rat Brain Dopamine and Muscarinic Receptors after Chronic Alcohol Intake
Authors: Syvälahti E. K. G. , Hietala J. , Röyttä M. , Grönroos J.
Published: March 2009

Abstract:The effect of 32 weeks' alcohol treatment on the number and affinity of dopamine and muscarinic receptor sites in rat striatum were measured using3H‐spiperone and3H‐quinuclidinylbenzilate (3H‐QNB) as radioligands. The number of dopamine receptor sites was 38 per cent and the number of muscarinic receptor sites 36 per cent lower in the alcohol group than in control rats. The differences in receptor affinities were less marked. In conclusion, a long‐term alcohol intake with rather moderate doses seems to induce a pronounced down‐regulation in dopamine and muscarinic receptor systems in rat striatum.
4‐Aminosalicylic Acid, in Contrast to 5‐Aminosalicylic Acid, has No Effect on Arachidonic Acid Metabolism in Human Neutrophils, or on the Free Radical 1,1‐Diphenyl‐2‐picrylhydrazyl
Authors: Nielsen O. H. , Ahnfelt‐Rønne I.
Published: March 2009

Abstract: 5‐Aminosalicylic acid seems to be the active moiety of sulfasalazine in the treatment of chronic inflammatory bowel disease. Even if the precise mode of action is obscure, it is assumed that two of the main mechanisms are inhibitory effects on the lipoxygenation of arachidonic acid and interaction with free radicals. As 4‐aminosalicylic acid has been claimed to be beneficial in the topical treatment of ulcerative colitis, it was tested whether this drug possesses any influence on the 5‐lipoxygenase activity in human neutrophils in vitro or whether it acts as a radical scavenger. The change of the amino residue from carbon‐5 to carbon‐4 abolished the effect in the two systems tested. The reported clinical observations on 4‐aminosalicylic acid in the treatment of chronic inflammatory bowel disease remain to be confirmed and cannot be explained by interference with arachidonic acid metabolism or free oxygen radicals.
Teratogenicity and in Vitro Mutagenicity Studies on Nonoxynol‐9 and −30
Authors: Meyer O. , Andersen P. Haubro , Hansen E. V. , Larsen J. C.
Published: March 2009

Abstract: Polyoxyethylene alkylphenols (PA) are a group of non‐ionic surfactants with a widespread use, As part of the safety evaluation of PA a teratology study with nonoxynol‐9 and −30 (NP‐9 and NP‐30) administered perorally and epicutaneously to rats was performed. In addition the mutagenicity of NP‐9 was tested in the Ames test. Treatment of pregnant rats with NP‐30 (up to 1 g/kg b.wt./day, orally) did not reveal any signs of adverse effects. Pregnant rats given 250 mg or 500 mg NP‐9/kg b.wt./day orally exhibited a statistically significant decrease in weight gain. A concominant effect in these dams on reproduction, and an increase in the incidence of extra ribs and dilated pelvic cavity in their foetuses was interpreted as a consequence of a toxic effect of high doses of NP‐9. No clear cut effect was observed when pregnant rats were dosed epicutaneously with up to 500 mg of NP‐9/kg b.wt./day. A slight but persistent response in one tester strain in the Ames test was not interpreted as a clear mutagenic effect of NP‐9.
Intestinal Absorption of Chloral Hydrate, Free Trichloroethanol and Trichloroacetic Acid in Dogs
Authors: Hobara Tatsuya , Kobayashi Haruo , Kawamoto Toshihiro , Iwamoto Susumu , Sakai Tsunemi
Published: March 2009

Abstract:In order to examine the intestinal absorption of chloral hydrate (CH), free trichloroethanol (F‐TCE) and trichloroacetic acid (TCA), an intestinal circulation system in dogs was developed using jejunal, ileal and colonic loops, and solutions of CH, F‐TCE and TCA were circulated within them. The concentrations of these substances and their metabolites in the serum, urine, bile and circulates were then measured. In all groups, the fraction of water absorbed from the intestine was about 10% of the administered volume two hours after administration. The absorbed fraction of CH was about 50% in the jejunum and ileum, and about 40% in the colon. The absorbed fraction of F‐TCE was about 60% in the jejunum, 5(Mo%0 in the ileum and about 40% in the colon, while the figures for TCA were about 40–50%0 in the jejunum and about 3040% in the ileum and colon. The combined biliary and urinary excretion ratios of the administered substances and their respective metabolites to the total amounts absorbed from the intestine were about 25–30. for F‐TCE, 10–15. for CH and 0.1‐0.2% for TCA in all parts of the intestine two hours after administration.
Disulfiram Prevents Acetaminophen Hepatotoxicity in Rats
Authors: Jørgensen L. , Thomsen P. , Poulsen H. E.
Published: March 2009

Abstract:Hepatic necrosis due to an oral acetaminophen overdose (4.25 g/kg b.wt.) was prevented by pretreatment with disulfiram 100 mg/kg, given for 3 weeks or as a single dose. Twenty‐four hours after acetaminophen the impairment of hepatic function, measured as prothrombin index, and the depletion of hepatic glutathione were prevented. Hepatic cytochrome P‐450 levels were unchanged but cytochrome P‐450 mediated p‐nitroanisole demethylation was reduced by disulfiram pretreatment. Disulfiram pretreatment reduced 24 hour urinary excretion of acetaminophen‐mercapturate and ‐cysteine while excretion of ‐sulfate and ‐glucuronide was unchanged. After 72 hours acetaminophen induced hepatic necrosis were prevented. Identical observations were made in animals pretreated with disulfiram for 3 weeks. Five hours after acetaminophen overdose its irreversible binding to hepatic proteins was not changed. After 24 hours, however, it was increased in animals pretreated with a single disulfiram dose and unchanged in animals pretreated for 3 weeks. The protective mechanism of disulfiram after acetaminophen overdose is not mediated via a change in overall irriversible binding of acetaminophen to hepatic protein.
Subacute Toxicity of Monocrotophos and its Influence on Circulating Enzymes of Bubalus bubalis
Authors: Sandhu H. S. , Malik J. K.
Published: March 2009

Abstract: Oral administration of 0.5 mg/kg/day monocrotophos for 28 days caused death in one out of three animals. A dose of 2.0 mg/kg/day of monocrotophos was 100 percent lethal within 8–1. days after start of insecticide administration. Clinical symptoms were mainly characterised by ataxia, knuckling of limbs, progressive paralysis and prostration. Monocrotophos at both doses caused significant inactivation of erythrocyte cholinesterase (29.4‐50.8%) and caused significant elevation in the serum levels of aspartate and alanine aminotransferases.
Actions and Interactions of Indomethacin and Diazepam on Performance in Healthy Volunteers
Authors: Nuotto Esko , Saarialho‐Kere Ulpu
Published: March 2009

Abstract: Objective and subjective effects on performance of single oral doses of indomethacin (IM) 50 mg and 100 mg and diazepam (DZ) 10–1. mg, alone and in combination, were investigated in two double‐blind studies conducted with parallel groups of healthy drug‐naive student volunteers. Objective and subjective effects were measured at baseline as well as 0.5 and 1.5 hours after treatment. DZ significantly impaired performance in digit symbol substitution, letter cancellation, tracking and flicker fusion tests. It also induced exophoria and caused subjective (visual analogue scales) drowsiness, mental slowness, clumsiness and impaired overall performance. IM proved rather inactive when slightly impairing flicker fusion and digit substitution, and subjectively rendering the subjects clumsier. The combined effects of IM and DZ did not differ from those obtained with DZ alone. Both IM and DZ induced dizziness and their effects in this respect were additive when the drugs were used in combination. It is concluded that single therapeutic doses of indomethacin do not produce major psychomotor effects and do not in this respect increase the effects of diazepam. However, the feeling of dizziness, a side‐effect common to both these drugs, may be additive when the drugs are used in combination.
Inhibitor Panel Studies of Human Hepatic and Placental Cytochrome P‐450‐Associated Monooxygenase Activities
Authors: Pasanen Markku , Taskinen Taina , Sotaniemi Eero A. , Kairaluoma Matti , Pekonen Olavi
Published: March 2009

Abstract:1. A panel of nine inhibitors displaying some P‐450 isozyme specificity was used to characterize aryl hydrocarbon hydroxylase (AHH) and 7‐ethoxyresorufin 0‐deethylase (ERDE) activities in human liver and placentain vitroin comparison with liver enzymes from control, phenobarbital (PB) and 3‐methylcholanthrene (MC) treated rats. 2. SKF 525A and cimetidine inhibited more potently hepatic AHH than the placental enzyme. 7,8‐Benzoflavone inhibited more efficiently placental AHH than the hepatic enzyme, whereas ERDE was inhibited at the same level in both tissues. Quinine, quinidine, SKF 525A and metyrapone inhibited ERDE almost to the same extent in both tissues, but the variability was larger with the liver enzyme. Aminoglutethimide, debrisoquine or tetrahydrofuran did not inhibit AHH or ERDE significantly in either tissue. 3. When compared with inhibition profiles obtained with rat liver microsomes, the human hepatic and placental ERDE resembled most that of MC‐treated rat liver enzyme. Inhibition profile of placental AHH activity was also similar, but the inhibition characteristics of hepatic AHH activity resembled more closely control or PB‐induced rat liver. It also seems that isozymes for alcohol induction or debrisoquine hydroxylation do not contribute significantly to hepatic or placental AHH or ERDE. 4. The inhibitor panel selected on the basis of known pretreatment and isozyme specificity might be useful in the characterization of enzymes and metabolic biotransformations participatng in the metabolism of new substrates.
Rat Kidney Lysosomal Membrane Damage Induced by Suramin in Vitro and in Vivo
Authors: Kanji Musbau A.
Published: March 2009

Abstract:The effect of suramin, an acid naphthylamine, on rat kidney lysosomal membrane integrity was studied. Lysosomal particles were incubated with suramin (0.1‐0.4 mM) and light scattering behaviour of the mixtures were subsequently measured. There was a significant decrease (P< 0.005) in the amount of light absorbed in the presence of suramin compared to lysosomal particle suspension alone. This was accompanied by release of acid phosphatase, a lysosomal ‘marker’ enzyme, into the suspending medium. These effects were reduced in the presence of acetylsalicylic acid, a known lysosomal membrane stabilizer. Administration of suramin to rats resulted in loss of kidney acid phosphatase and lysozyme activities from the tissue. These results indicate labilization of rat kidney lysosomal membrane by suramin molecules bothin vitroandin vivo.
A Comparison of the Effect of Timegadine, Levamisole, and D‐Penicillamine on Human Neutrophil Metabolism of Endogenous Arachidonic Acid and Chemotaxis
Authors: Nielsen O. H. , Ahnfelt‐Rønne I. , Elmgreen J.
Published: March 2009

Abstract: The effect of timegadine, a novel experimental antirheumatic drug, on human neutrophil (PMN) 5‐lipoxygenase activity and leukotriene B4 (LTB4) chemotaxis was compared with that of two second‐line antiinflammatory drugs, D‐penicillamine and levamisole. 1‐14C‐Arachidonic acid (AA) was incorporated into the purified cells until steady state conditions were obtained. After preincubation with serial dilutions of the three drugs, AA release and metabolism was stimulated with calcium ionophore A23187. The radioactive eicosanoids released were extracted and separated by thin‐layer chromatography, followed by autoradiography and quantitative laser densitometry. Chemotaxis of PMNs towards LTB4 was measured in a modified Boyden chamber. Timegadine showed dose‐dependent inhibition of both the 5‐lipoxygenase pathway (IC50 3.4 × 10‐5 M), and of chemotaxis (IC50 3 × 10‐4 M). Inhibition of the release of AA from phospholipids, however, occurred only at therapeutically irrelevant doses (millimolar concentrations). Levamisole and D‐penicillamine did not inhibit any of the cell functions investigated. Inhibition of both neutrophil motility and cellular synthesis of pro‐inflammatory eicosanoids, may thus contribute to the clinical effects of timegadine in rheumatoid arthritis.
Cardiovascular Effects of the Novel Cardiotonic Agent DPI 201–10. in the Anaesthetized Rat
Authors: Fraser M. , Törnquist K. , Sellin L. C.
Published: March 2009

Abstract: DPI 201–10. (4‐[3‐(4‐diphenylmethyl‐1‐piperazinyl)‐2‐hydroxypropoxy]‐1H‐indole‐2‐carbonitrile) was given intravenously to anaesthetized male rats. DPI caused an increase in left ventricular dP/dt (LV dP/dt), giving a significant increase at 0.03 μmol/kg. At this dose DPI had no effect on either mean arterial pressure (MAP) or heart rate (HR). At higher doses, MAP decreased transiently. At 0.3 and 1 μmol/kg, HR was decreased. The results indicate that DPI produces positive inotropic and negative chronotropic effects in the anaesthetized rat.
The Effect of Estramustine, Nor‐nitrogen Mustard and Tauromustine on Macromolecular Labelling in the Human Prostatic Tumour Cell Line 1013L
Authors: Kruse Elisabeth , Hartley‐Asp Beryl
Published: March 2009

Abstract:To further clarify the mode of action of estramustine, the influence on macromolecular synthesis in the human prostatic tumour cell line 1013L was investigated. Cell treatment with estramustine, nor‐nitrogen mustard and tauromustine, followed by radioactive nucleotide and leucine incorporations, as a measure of RNA, DNA and protein labelling, were carried out. The initial effect of estramustine clearly differed from that obtained after treatment with nor‐nitrogen mustard and tauromustine. No inhibition of DNA synthesis was found whereas an inhibition of overall RNA synthesis was predominant. Adaption of an established RNA separation method was used in an indepth study of RNA labelling after estramustine treatment. An inhibition of 29S, 18S and 4–7S RNA was found after estramustine treatment, indicating disturbances in either RNA processing or RNA transport. The lack of 45S RNA labelling additionally indicates pre‐ribosomal inhibition.
Pinacidil Uptake and Effects in the Isolated Rabbit Heart
Authors: Nielsen Claus Brøckner , Mellemkjær Søren , Nielsen‐Kudsk Folmer
Published: March 2009

Abstract:The myocardial accumulation of pinacidil showed one‐compartment characteristics with a half‐time of 1.11 min., whereas the disposition followed three‐compartment kinetics with half‐times for the relevant two redistributory and the terminal phases of 0.39, 1.51 and 5.44 min., respectively. At a steady‐state drug concentration in the perfusate of 6.12 nmol ml−1, the average concentration of pinacidil in the myocardium was 20.6 nmol g−1. The accumulated amount could predictically be referred with 57% to a central and 31 and 12% to two peripheral (deeper) drug pools. The pharmacodynamic effects of pinacidil in the isolated perfused rabbit heart were studied at stepwise increasing concentrations from 0.15 to 100 μM. Coronary flowrate increased initially up to 24.5% at 1.5 μM pinacidil and then gradually decreased. Amplitude and velocity of contraction were both inhibited in a biphasic way up to 92.7 and 94.1%, respectively. Apparent dynamic steady states developed within 13–15 min. The computer‐derived inhibitory Em‐values related to the first phase were 49.2 and 52.4% and those related to the second phase were 111.7 and 108.3%, respectively. Heart frequency decreased monophasically and exhibited an inhibitory Em‐value of 19.6%. Oxygen consumption decreased at pinacidil concentrations higher than 15 μM and the Em‐value was 69.7%. The frequency‐corrected QT‐interval decreased biphasically and the related inhibitory Em‐values were 8.6 and 58.7%. The QRS‐interval did not change and the PQ‐interval only showed a minor increase at the highest pinacidil concentration. Our findings are compatible with the concept of pinacidil being a potassium channel opener.
Guanethidine‐Induced Sympathectomy in the Nude Rat
Authors: Juul Anders , Juul Per , Christensen Henning Bjørn
Published: March 2009

Abstract: Guanethidine sulphate 40 mg/kg was administered intraperitoneally daily for 14 days to normal Lewis rats and athymic nude rats of a Lewis background (rnu/rnu). Histological examination of the superior cervical ganglia demonstrated a pronounced chromatolysis of the neurones and a loss of the major part of the nerve cells accompanied by an increased number of small mononuclear inflammatory cells. The extent of chromatolysis and nerve cell death induced by guanethidine did not differ between normal and nude rats, whereas the increase of the number of mononuclear cells was lower in the nude rats than in the normal rats (163 and 268 per cent respectively of the saline treated controls, P<0.01). Since guanethidine induced nerve cell death in the T‐cell deficient nude rat to the same extent as in normal rats, it is concluded, that the effect is caused by either a thymus‐independent immune‐response or by a direct toxic effect.
Distribution of Aluminium Following Intraperitoneal Injection of Aluminium Lactate in the Rat
Authors: Costantini Sergio , Giordano Rosa , Ioppolo Alfredo , Mantovani Alberto , Ballanti Paola , Mocetti Patrizia , Bonucci Ermanno
Published: March 2009

Abstract: An animal experiment was performed to evaluate the absorption and distribution of aluminium in serum and tissues of normal rats. The animals were intraperitoneally injected with an aluminium lactate solution at a pH adjusted to 7.0. Before starting, a short preliminary study was carried out in order to verify the validity of the treatment with aluminium lactate instead of aluminium chloride at endogenous pH 3.4. Thirty‐one rats were used in the main experiment, divided in four groups. In treated animals, the total A1‐administered dose was 75.6 mg during 78 days of treatment. Furthermore, to evaluate the influence of the parathyroid hormone on A1 absorption and/or distribution, 200 USP/rat of parathyroid hormone extract (PTH) were also administered during the last 5 days of the experiment. Aluminium content in serum, tibia, rib, brain, liver, muscle, kidney and spleen was determined. Calcium analysis in serum and bone was also performed. The highest concentrations of aluminium were found in liver and spleen, whereas the lowest level was found in the brain. The PTH effect on A1 absorption was evident in brain and bone.
Effect of Diazoxide and Hydralazine on Intestinal Transit and Blood Pressure in the Rat
Authors: Pober Zalmon , Johnson David A. , Moya‐Huff Fernando A. , Maher Timothy J.
Published: March 2009

Abstract:This study examines the effects of diazoxide and hydralazine on gastrointestinal and vascular smooth muscle. The effect of the drugs administered individually and in combination was determined on small intestinal transit and blood pressure in adult male Sprague‐Dawley rats. Both diazoxide and hydralazine produced dose‐dependent decreases in the ratio of intestinal transit to total length. Additionally, combinations of various doses of hydralazine and diazoxide produced a greater than simple summation of the inhibitory effects on intestinal transit. The combination of diazoxide and hydralazine produced only a simple additive effect on mean arterial pressure.
Histamine Receptors in the Smooth Muscle of Human Internal Mammary Artery and Saphenous Vein
Authors: Schoeffter Philippe , Godfraind Théophile
Published: March 2009

Abstract:The effects of histamine were characterized and compared in the vascular smooth muscle of two human isolated blood vessels, the human internal mammary artery (HIMA) and the human saphenous vein (HSV). Segments of these vessels were obtained during aortocoronary bypass surgery and their intimal surface was rubbed in order to eliminate any possible influence of the endothelium. Histamine contracted both types of vessels in a concentration‐dependent manner and this effect was antagonized by the H1receptor antagonists mepyramine and cicletanine. In the case of HIMA only this antagonism was found to be competitive (pA2values of 9.3 and 7.7 for mepyramine and cicletanine, respectively). Histamine‐induced contractions were not significantly affected by phentolamine (0.3 μM). In HSV, but not HIMA, indomethacin (5 μM) significantly depressed histamine‐induced contractions (by about 30%). In the presence of the H2receptor antagonist cimetidine (10 μM), concentration‐response curves of histamine‐induced contractions were significantly shifted to the left in both HIMA and HSV, suggesting the presence of H2receptors mediating relaxation. HIMA and HSV precontracted by noradrenaline could be partially and concentrationdependently relaxed by histamine, only in the presence of a H1receptor antagonist. This relaxation was inhibited by cimetidine. The results show that in de‐endothelialized HIMA and HSV histamine induced mainly contraction which is sensitive to the H1receptor antagonists. Only in HIMA, nevertheless, was competitive antagonism established. In addition, histamine‐induced relaxation, antagonized by cimetidine, could be demonstrated in both precontracted vessels, indicating the presence of H2receptors.
Teratogenic Effects of Some Calcium Channel Blocking Agents in Xenopus Embryos
Authors: Burgess Ann M. C. , Vere D. W.
Published: March 2009

Abstract: Xenopus embryos, treated for three days from the early cleavage stage with the calcium channel blocking drugs nifedipine, diltiazem, verapamil or nicardipine continue to develop in water. By the seventh day many developmental abnormalities appear, the most reproducible affecting the central nervous system, failure of forebrain development, synophthalmia and neural tube defect. Other anomalies include failure of mandibular growth and malrotation of the gut. Failure of water and electrolyte transport are indicated by severe oedema in some animals. The defects appear to relate to calcium ion antagonism, and provide a pharmacological model for some forms of teratogenesis in which large populations can be studied readily.
Effects of Toluene on Protein Synthesis and the Interaction with Ethanol in Hepatocytes Isolated from Fed and Fasted Rats
Authors: Smith‐Kielland Anne , Ripel Åse , Gadeholt Gaut
Published: March 2009

Abstract: The effects of three different concentrations (about 10, 100 and 1000 μM) of toluene on protein synthesis were studied in hepatocytes isolated from fed and fasted rats after 60 and 120 min. of incubation. The interaction between ethanol (60 mM) and the low and high toluene concentrations were also tested. To measure protein synthesis, 14C‐valine was used as the precursor amino acid. Total valine concentration was 2 mM to ensure near‐constant specific radioactivity of precursor. Toluene concentrations were measured by head‐space gas chromatography. Protein synthesis was unchanged in the presence of low toluene concentrations. Intermediate toluene concentration decreased protein synthesis by about 20% and high toluene concentration decreased protein synthesis by about 60%. Protein synthesis was similar in cells from fed and fasted rats. Ethanol alone inhibited protein synthesis by 20–30%, more in fasted than in fed rats. Toluene and ethanol in combination inhibited protein synthesis additively. The high toluene concentration with or without ethanol appeared to inhibit synthesis/secretion of export proteins in hepatocytes from fasted rats. In conclusion, our study indicates that toluene in relatively high concentrations inhibits general protein synthesis in isolated rat hepatocytes. Toluene and ethanol seems to inhibit protein synthesis additively.
Blood Gas Tensions, Acid‐Base Status and Cardiovascular Function in Miniature Swine Anaesthetized with Halothane and Methoxyflurane or Intravenous Metomidate Hydrochloride
Authors: Svendsen P. , Carter A. M.
Published: March 2009

Abstract:Göttingen mini‐pigs were given atropine and anaesthetized with one of the following drug combinations: 1) azaperone+metomidate, 2) acepromazine+thiopentone for endotracheal intubation, followed by halothane+methoxyflurane in oxygen. Respiration rate, arterial O2and CO2tensions, arterial pH, mean arterial blood pressure and heart rate were recorded at 15 min. intervals from 30 to 120 min. after the induction of anaesthesia. The azaperone‐metomidate combination, which requires continuous intravenous access, caused a mild respiratory acidosis, but acid‐base status was stable, whereas blood pressure and heart rate rose steadily throughout the observation period. The second combination depressed respiratory and cardiovascular function, but the condition of the animals did not deteriorate further during 2 hrs of surgical anaesthesia. Endotracheal intubation for inhalation anaesthesia should, however, be performed after a single injection of metomidate, as thiopentone tended to cause respiratory arrest.
Adenosine Triphosphate Blocks Opiate Withdrawal Symptoms in Rats and Mice
Authors: Gomaa Adel A. , Moustafa S. A. , Farghali A. A.
Published: March 2009

Abstract:The effect of adenosine triphosphate (ATP) on the expression of opiate withdrawal was examined using a chronic model of morphine‐dependence. ATP was studied for its ability to modify or block jumping in morphine‐abstinent mice. In mice administered 2 mg/kg ATP intravenously, the naloxone ED50 for withdrawal jumping increased by 11‐fold in comparison to saline‐treated mice. Nalaxone‐precipitated morphine‐withdrawal in the rats, has been shown to induce a specific pattern of intestinal hypermyoelectric activity and to increase the arterial blood pressure. Administration of ATP at dose of 1 and 2 mg/kg intravenously inhibited the induction of hypermyoelectric activity pattern in 80 and 100% of animals tested respectively. ATP also blocked the increase in mean arterial blood pressure seen during withdrawal in a dose‐dependent fashion. Investigations were carried out to determine if blocking of the α2‐adrenoreceptors with yohimbine would result in an alteration in antiwithdrawal action of ATP. Yohimbine reversed the effect of ATP in blocking naloxone‐precipitated withdrawal on the myoelectric activity of jejunum and colon, however, it failed to antagonize the effect of ATP on withdrawal jumping and to block the effect of ATP on the pressor response produced by naloxone in morphine‐dependent animals.
Inhibition of Acute CNS‐Tolerance to Hexobarbital and Prolongation of Hexobarbital Anaesthesia by Disulfiram Treatment in Rats
Authors: Nilsson Göran E. , Wahlström Göran
Published: March 2009

Abstract:In many studies disulfiram treatment has been found to prolong hexobarbital anaesthesia, but the underlying mechanisms have not been clarified. In the present study, the effect of disulfiram on the development of acute tolerance to hexobarbital was studied in 2 age groups of rats (80 and 130 days old). Acute tolerance was measured as the increase in the brain concentration of hexobarbital (in 4 brain regions) needed to keep the rats on a constant EEG‐monitored anaesthetic level for 1 hr. The effects of disulfiram on the metabolismin vitroand eliminationin vivoof hexobarbital were also measured. The results suggested that the prolonged hexobarbital anaesthesia found after disulfiram treatment was the result of an inhibition of at least two different mechanisms: (1) the ability of the brain to develop acute tolerance to hexobarbital, and (2) the metabolism of hexobarbital by the liver, the latter resulting in a decreased elimination of the anaesthetic from the brain. The impaired development of acute tolerance was apparent only in the older rats. The inhibition of hexobarbital metabolism was most obvious in the younger ones.
ACE‐Inhibitor‐Induced Enhancement of Spontaneous and IgE‐Mediated Histamine Release from Mast Cells and Basophilic Leukocytes and the Modulatory Effect of Capsaicin Sensitive Nerves
Authors: Lindgren Björn R. , Persson Karin , Kihlström Jan‐Erik , Andersson Rolf G. G.
Published: March 2009

Abstract:Frequently reported adverse inflammatory skin and airway reactions have been reported in subjects being medicated with angiotensin converting enzyme (ACE)‐inhibitors. Intradermally evoked wheal and flare reactions to ovalbumin, capsaicin and bradykinin, in ovalbumin sensitized guinea pigs, was previously demonstrated to be enhanced by pretreatment with the ACE‐inhibitor MK 422 (the active parent diacid of enalapril).In vitroresults from this study demonstrate that the ACE‐inhibitor MK 422 degranulated guinea pig lung and skin mast cells as well as human basophils, and enhanced allergen‐evoked histamine release. Local capsaicin pretreatmentin vivoof guinea pig skin decreased spontaneous and allergen‐triggered release of histaminein vitrofrom skin mast cells. No clear enhancing effect of MK 422 was seen on the allergen‐triggered histamine releasein vitrofrom capsaicin pretreated skin, and the spontaneous release was unaffected by the ACE‐inhibitor. The allergen‐triggered wheal and flare reaction in ovalbumin sensitized guinea pigs was potentiated by MK 422 and the late phase reaction of the inflammatory response was especially augmented. Capsaicin pretreatment of the guinea pigs abolished this late phase reaction as well as the inflammatory enhancing effect of MK 422. Ourin vitroresults from capsaicin pretreated skin indicate that the reduced inflammatory responsein vivoin capsaicin pretreated skin is due not only to capsaicin induced depletion of neuropeptides from sensory nerves, but also to secondary degranulation of mast cells by one or more of these peptides.
Characterization of the Discriminative Stimulus Properties Induced by 5‐HT1and 5‐HT2Agonists in Rats
Authors: Arnt Jørn
Published: March 2009

Abstract:The effect of different serotonin (5‐HT) agonists and antagonists on the discriminative stimulus properties (cue) induced by 8‐hydroxy‐2‐(di‐n‐propylamino)‐tetralin (8‐OHDPAT), 1‐(m‐trifluoromethylphenyl)piperazine (TFMPP) and d‐LSD (d‐lysergic acid diethylamide) has been investigated. The 8‐OHDPAT cue was mimicked by the 5‐HT1Aagonists ipsapirone, buspirone, gepirone and partially by 5‐methoxy‐N,N‐dimethyltryptamine and d‐LSD. 5‐HT1B(TFMPP and RU 24969) and 5‐HT2agonists (DOM, DOI and quipazine) were ineffective and induced disruption of responding. The 8‐OHDPAT cue was antagonized by spiroxatrine and partially by (‐)‐alprenolol, whereas selective antagonists of 5‐HT2(ketanserin and ritanserin), 5‐HT3(ICS 205–930), α1‐adrenergic (prazosin) and β‐adrenergic receptors (ICI 118.551) were ineffective. The TFMPP cue was mimicked by RU 24969 and partially by quipazine. Other compounds were ineffective. Only (‐)‐alprenolol antagonized the effect of TFMPP. The d‐LSD cue was mimicked by DOM, DOI, quipazine, 5‐methoxy‐N,N‐dimethyltryptamine and partially by ipsapirone, TFMPP and RU 24969. The 3 latter compounds and 5‐HT1Aagonists induced disruption of responding. The d‐LSD cue was antagonized by ketanserin and ritanserin, but not by the other antagonists mentioned above. The specific inhibitor of 5‐HT uptake citalopram was not able to substitute for any of the 3 agonists. It is concluded that the drug discrimination technique can be used to identify selective agonists and antagonists of 5‐HT receptor subtypes. Compounds with mixed effects on 5‐HT receptor subtypes can also be identified. These show additional effects on reaction time and often disrupt responding at higher dosages.