bluuebunny/crossref_metadata_2025 huggingface dataset:
Elimination Half‐life of Methanol During Hangover
Authors: Jones A. W.
Published: March 2009

Abstract:This paper reports the elimination half‐life of methanol in human volunteers. Experiments were made during the morning after the subjects had consumed 1000–1500 ml red wine (9.5% w/v ethanol, 100 mg/1 methanol) the previous evening. The washout of methanol from the body coincided with the onset of hangover. The concentrations of ethanol and methanol in blood were determined indirectly by analysis of end‐expired alveolar air. In the morning when bloodethanol dropped below the Km of liver alcohol dehydrogenase (ADH) of about 100 mg/1 (2.2 mM), the disappearance half‐life of ethanol was 21, 22, 18 and 15 min. in 4 test subjects respectively. The corresponding elimination half‐lives of methanol were 213, 110, 133 and 142 min. in these same individuals. The experimental design outlined in this paper can be used to obtain useful data on elimination kinetics of methanol in human volunteers without undue ethical limitations. Circumstantial evidence is presented to link methanol or its toxic metabolic products, formaldehyde and formic acid, with the pathogenesis of hangover.
Plasma Concentration Following Oral Administration of Di‐and Flucloxacillin in Infants and Children
Authors: Bergdahl Sven , Eriksson Margareta , Finkel Yigael
Published: March 2009

Abstract: The bioavailability of commercial liquid preparations of di‐ and flucloxacillin was compared in infants and children. The plasma concentrations following a dose of 12.5 mg/kg were equal within the two age groups. Infants 0‐1 months old, however, demonstrated a better absorption than older children.
Effects of Diazepam on Muscarinic Acetylcholine Receptor Binding in Vivo and on Oxotremorine‐induced Tremor and Hypothermia in Mice
Authors: Nordgren I. , Lundgren G. , Karlén B.
Published: March 2009

Abstract:Diazepam has previously been shown to affect the acetylcholine synthesizing system in mouse brain. This paper reports studies on the effect of diazepam on muscarinic receptor density and on pharmacological effects of oxotremorine. The receptor density was studied using a new technique that allows such studies to be performedin vivounder physiological conditions. The method is based on the fact that L‐hyoscyamine, the active antipode of atropine, binds specifically to muscarinic receptors in the brain, and can be measured with high sensitivity by gas chromatography‐mass spectrometry. Diazepam was found to modify the binding properties of muscarinic receptors in CNS, thereby decreasing the functional receptor pool. It also prevented tremor induced by the muscarinic agonist oxotremorine. Diazepam could however not prevent the hypothermia induced, but rather accentuated this effect of oxotremorine. It is concluded that diazepam, directly or indirectly, influences the effect of cholinergic stimulators by modulating the size of the muscarinic receptor pool.
Stimulation of Inositol Phospholipid Breakdown in Rat Cortical and Hippocampal Miniprisms by Noradrenaline, 5‐Hydroxytryptamine and Carbachol: Some Methodological Aspects
Authors: Fowler Christopher J. , Court Jennifer A. , Tiger Gunnar , Björklund Per‐Erik , Candy John M.
Published: March 2009

Abstract:After incubation of miniprisms from rat cerebral cortex or hippocampus with3H‐myo‐inositol, labelling of the phospholipid (“Lipid”) and inositol phosphate (“InsP”) fractions was found. Inositol phospholipid hydrolysis (“PI breakdown”) was stimulated by noradrenaline, 5‐hydroxytryptamine and carbachol. Expressing data as InsP/(Lipid + InsP) was found to be a superior measure of the rate of PI breakdown compared with the more commonly used InsP d.p.m. unit, since the former was found to be independent of the volume of the miniprism aliquot used and the degree of labelling of inositol phospholipids. The PI breakdown responses to noradrenaline, 5‐hydroxytryptamine and particularly carbachol were found to be enhanced by increasing the assay [K+] from 5.88 mM to 18.2 mM. Storage of hippocampal samples at — 70° by the “slow freeze ‐ fast thaw” method of Hardyet al.(1983) resulted in a decreased degree of labelling of the Lipid and InsP fractions and a loss of the PI response to noradrenaline when assayed at a [K+] of 5.88 mM, but a reasonable response was seen in these samples at an assay [K+] of 18.2 mM. The temperature of the Krebs‐Henseleit buffer used in the preparation of the miniprisms was found to be important for the PI breakdown response.
Acute Toxicity Studies of Aluminium Compounds: Antidotal Efficacy of Several Chelating Agents
Authors: Llobet Juan M. , Domingo Jose L. , Gómez Mercedes , Tomás José M. , Corbella Jacinto
Published: March 2009

Abstract:Four aluminium compounds ‐nitrate, chloride, sulphate and bromide‐ were administered orally and intraperitoneally to rats and mice. The LD50 ‐values (14 days) were determined. The majority of deaths occurring during the first four days. The clinical and physical signs appearing after intoxication include among others lethargy, decreased locomotor activity, piloerection, weight loss and perorbital bleeding. After 14 days no alterations in liver and renal functions were detected in the animals which received intraperitoneally the LD50 ‐values of aluminium nitrate as a single dose. Aluminium concentrations were highest in liver and spleen. No histopathological lesions could be observed. To compare the efficacies of nine chelating agents on the toxicity of aluminium in mice, the therapeutic index and the therapeutic effectiveness of each chelating agent have been calculated. Malic, succinic, oxalic and malonic acids showed the best results with malic and succinic acids being the most effective. Deferoxamine mesylate (DFOA), sodium salicylate, L‐cysteine and citric acid were not so effective as antidotes for acute aluminium toxicity. Aurin tricarboxylic acid (ATCA) should not be used due to its high toxicity.
The Increasing and Decreasing Effects of Aromatic Hydrocarbon Solvents on Pulmonary and Hepatic Cytochrome P‐450 in the Rat
Authors: Pyykkö Kaija , Paavilainen Sari , Metsä‐Ketelä Timo , Laustiola Kai
Published: March 2009

Abstract:The effects of pretreatment with benzene and various methylbenzenes, ethyl‐ and propylbenzene, cumene and styrene on hepatic and pulmonary microsomal enzymes were studied in male rats. In the lungs, all the substituted benzenes, but not benzene itself, decreased cytochrome P‐450 concentration, and most of them also decreased 7‐ethoxycoumarin O‐deethylase activity, whereas 7‐ethoxyresorufin O‐deethylase activity was increased by the same treatment. The change in aryl hydrocarbon hydroxylase activity was negligible. Neither NADPH ‐ cytochrome c reductace activity, nor cytochrome b5concentration were changed after hydrocarbon treatment. In the liver, all the compounds studied, except for benzene, increased 7‐ethoxycoumarin O‐deethylase and 7‐ethoxyresorufin O‐deethylase, and most of them also cytochrome P‐450, aryl hydrocarbon hydroxylate and NADPH ‐ cytochrome c reductase. The effect on cytochrome b5in the liver was less marked. In the liver, all the monooxygenases studied seemed to be inducible by alkylbenzenes and styrene, whereas the effect was selective in the lung; depending on the monooxygenase, the activity can increase, decrease or remain unchanged.
Chronic Treatment with Antidepressant Drugs and ECT Differentially Modifies the Hypothermic Action of Clonidine and Guanfacine
Authors: Danysz Wojciech , Minor Bruce G. , Mohammed Abdul , Pucilowski Olgierd , Plaznik Adam , Kostowski Wojciech , Post Claes , Archer Trevor
Published: March 2009

Abstract:The hypothermia inducing action of clonidine and guanfacine was abolished by yohimbine and idazoxan pretreatment which suggests an α2‐adrenoceptor involvement in this effect. The effects of acute and chronic treatment with the antidepressant drugs desipramine (DMI), amitriptyline (AMI), maprotiline (MAP), mianserin (MIAN), iprindol (IPR), alaproclate (ALA) and electroconvulsive treatment (ECT) on the hypothermic action of the α2‐adrenoceptor agonists clonidine and guanfacine were studied. Acute administration of MIAN potentiated clonidine induced hypothermia whereas acute MIAN, IPR and ALA potentiated guanfacine induced hypothermia. Repetitive DMI, AMI and MAP treatment attenuated clonidine‐induced hypothermia whereas guanfacine‐induced hypothermia was potentiated by chronic treatment with DMI, AMI, MAP and MIAN. ECT applied without anaesthesia attenuated both clonidine and guanfacine hypothermia, however, under ethyl ether anaesthesia ECT was effective only towards guanfacine hypothermia. This discrepancy is discussed in terms of the relative selectivity of the agonists used, the reliability of agonist studies for indexing receptor function, and possible pharmacokinetic interaction.
Combined Effect of Low Doses of Propranolol and Ethanol on Cardiac Function: A Comparative Study by Radionuclide Ventriculography in Conscious Dogs
Authors: Ahonen E. , Tahvanainen K. , Länsimies E. , Nevalainen T. , Hartikainen J. , Hakumäki M.
Published: March 2009

Abstract:Trained, chronically instrumented, conscious dogs were used to evaluate the effect of propranolol (PRO), ethanol (ETH) or their combination (P + E) on the left ventricular (LV) function by first‐pass radionuclide ventriculography (RNV). Six dogs were trained prior to a sterile left thoracotomy, where a left atrial catheter was implanted. After recovery of four days RNV was carried out by injecting a bolus of technetium‐99m diethylenetriamine pentaacetic acid via the catheter to the left atrium. The data was collected for 12 sec. to a computer by frame rate of 20 frames/sec. from left lateral view of the dog. The experiments were performed both in four‐leg standing and in 60‐degree head‐up tilted positions. After control measurements the data were obtained with 0.5 mg/kg of PRO, 0.45 g/kg of ETH and their combination. The P + E combination increased significantly LV end‐diastolic and end‐systolic volumes, whereas LV peak ejection rate and ejection fraction were decreased. Upright position diminished the LV volume and increased heart rate, while ejection fraction and cardiac output remained unchanged. The first‐pass RNV method proved to be promising for measuring the cardiac pharmacological effects in conscious dogs. The combination of propranolol and ethanol in low doses induced an unexpectedly strong depression of LV function, which is supposed to be followed of latent cardiac depressing effect of ETH revealed by blockade of compensatory adrenergic mechanisms with PRO.
The Anaesthetic Potency of 3α‐Hydroxy‐5α‐pregnan‐20‐one and 3α‐Hydroxy‐5β‐pregnan‐20‐one Determined with an Intravenous EEG‐Threshold Method in Male Rats
Authors: Norberg Lennart , Wahlström Göran , Bäckström Torbjörn
Published: March 2009

Abstract:Two progesterone metabolites 3α‐hydroxy‐5α‐pregnan‐20‐one (5‐α) and 3α‐hydroxy‐5β‐pregnan‐20‐one (5‐β) were investigated for anaesthetic potency in male rats with an EEG‐threshold method. Dose rate curves were obtained by infusing 5‐α and 5β intravenously with different rates until an EEG‐criterion (a burst suppression of one sec. or more, the “silent second”) was seen in the EEG. The potency of the investigated drugs has been estimated by comparing threshold doses at optimal infusion rates. 5‐α and 5‐β were tested on both young (44 to 46 days) and adult (109 to 118 days) rats. The relation between age and the anaesthetic sensitivity of 5‐β was tested by weekly threshold determinations. 5‐α and 5‐β infused separately with different infusion rates gave almost V‐shaped dose rate curves. The optimal infusion rate was in all age groups 2 mg/kg/min. In young rats 5‐α (6.7 mg/kg) was more potent than 5‐β (8.9 mg/kg). In adult rats the sensitivity was increased but the relation in potency between 5‐α (5.1 mg/kg) and 5‐β (6.6 mg/kg) was unchanged. With 5‐β the main change in this age‐related increase in anaesthetic sensitivity was seen between 49 and 70 days of age. Both 5‐α and 5‐β exhibited an excitatory action seen as jerks during induction of the EEG‐criterion.
Alterations in Peripheral and Central Dopamine Receptor Sensitivity after Subchronic Treatment with Fluphenazine and Sulpiride
Authors: Hietala J. , MacDonald E. , Syvälahti E. , Scheinin M.
Published: March 2009

Abstract:The effects of subchronic treatment with the antipsychotic drugs fluphenazine and sulpiride on the sensitivity of peripheral neuronal dopamine receptors and central dopamine autoreceptors were evaluated. The ability of apomorphine, a dopamine agonist, to inhibit electrically induced sympathetic vasoconstriction in pithed rats, and apomorphine‐induced inhibition of spontaneous locomotor activity in awake rats were used as indices of peripheral and central dopamine receptor sensitivity, respectively. A single injection of fluphenazine decanoate, a long‐acting preparation of fluphenazine, enhanced the central locomotor inhibitory effect of low doses of apomorphine 4 and 6 weeks after drug administration, whereas the antidopaminergic effect on peripheral dopamine receptors was prolonged and persisted at least up to 6 weeks. In another set of experiments rats were treated with fluphenazine hydrochloride and sulpiride for 10 days and subsequently challenged with apomorphine after various withdrawal times. Both antipsychotic drugs augmented the inhibitory effect of apomorphine in the periphery, although the time courses of the potentiation were different. Both treatments also enhanced the locomotor inhibitory effect of apomorphine. These results are in line with our previous finding that long‐term treatment with dopamine antagonists can induce neuronal dopamine receptor up‐regulation also outside the central nervous system. Peripheral neuronal dopamine receptors thus show similar adaptive responses to long‐term blockade as central dopamine autoreceptors, and may serve as a useful experimental model in studies concerned with mechanisms of dopaminergic autoregulation in the central nervous system.
Extrahepatic Metabolism of Chloral Hydrate, Trichloroethanol and Trichloroacetic Acid in Dogs
Authors: Hobara Tatsuya , Kobayashi Haruo , Kawamoto Toshihiro , Iwamoto Susumu , Sakai Tsunemi
Published: March 2009

Abstract:To examine the details concerning that part of TRI metabolism which was carried out by the extrahepatic organs, we studied the extrahepatic metabolism of chloral hydrate (CH), free‐trichloroethanol (F‐TCE) and trichloroacetic acid (TCA) using a method developed in our laboratory. Bypass and non‐bypass dogs were given CH, F‐TCE and TCA, and we compared the concentrations these substances and their metabolites in the serum and urine of the two groups of animals. In the bypass dogs, F‐TCE, TCA and conjugated‐trichloroethanol (Conj‐TCE) appeared in the blood and urine 30 min. after the CH administration, and TCA and Conj‐TCE appeared 30 min. after the F‐TCE. All levels of administered substance were higher in bypass dogs than in non‐bypass dogs, and the compounds were metabolized in small amounts in the extrahepatic organs compared with the liver. Therefore, administered substances remained at high levels in the serum and were excreted in large amounts in the urine in the form of unchanged substances. The metabolized percentage volumes of CH to TCA in the bypass dogs were 10–20%, and those of F‐TCE to TCA were very small, while these percentage values of CH to F‐TCE were the same or slightly smaller, respectively. Moreover, trichloroethylene (TRI) acts to decrease the leukocyte count in the blood, but the TRI metabolites described above do not have this function.
Elimination and Toxicity of Perfluorooctanoic Acid during Subchronic Administration in the Wistar Rat
Authors: Hanhijärvi Hannu , Ylinen Markku , Kojo Anneli , Kosma Veli‐Matti
Published: March 2009

Abstract: Perfluorinated fatty acids have been used commercially as corrosion inhibitors, wetting agents, fire extinguishers and surface active agents. In an earlier study the male rats were more susceptible to the toxic effects of perfluorooctanoic acid (PFO) than females. PFO‐concentrations in the plasma suggested that there was a sex related difference in the urinary elimination rate. Active tubular secretion was observed only in the female kidney. The aim of the present study was to compare the urinary elimination of PFO between the two sexes during subchronic administration to the Wistar rat. PFO was administered by gavage to 48 newly‐weaned animals at 0 mg/kg, 3 mg/kg, 10 mg/kg and 30 mg/kg for 28 consecutive days. The urine was collected on the 7th and 28th day of the study. At the end of the study, blood was collected by cardiac puncture. At necropsy, tissue specimens for histopathologic examination were collected from the controls and from the group receiving 30 mg/kg of PFO daily. Unlike the female rats, on the 7th day of the study all three groups of male rats excreted significant less PFO than their daily dose of PFO, which suggested that the males had not reached a steady state by seven days: On the 28th day, the males excreted an amount of PFO equal to their daily dose. The PFO concentrations in the plasma of the male animals suggested that the binding sites of PFO may become saturated at the chronic daily dose level of 30 mg/kg. Although the PFO concentrations in the plasma were significantly higher in the male animals, no significant differences were observed at necropsy or in a histopathological findings between the sexes.
Single Dose Pharmacokinetics of Etretin and Etretinate in Psoriatic Patients
Authors: Larsen Frederik Grønhøj , Jakobsen Preben , Larsen Christian Grønhøj , Nørgaard Aage , Kragballe Knud , Nielsen‐Kudsk Folmer
Published: March 2009

Abstract: Etretin, an aromatic retinoic acid derivative, has recently been introduced as a possible substitute for etretinate in the treatment of severe psoriasis and other dyskeratoses. A total of nine patients with psoriasis of either sex in the age range 23–76 years was investigated after single dose oral drug administration, six were given 40 mg of etretin and three 40 mg of etretinate. A newly developed reversed‐phase HPLC method was applied for simultaneous determination of etretin and etretinate in plasma. In patients receiving etretinate, the lag‐time i.e. the time elapsing until appearance of first‐order drug absorption was 1.24$pL0.27 for the parent drug and 0.69 hrs$pL0.16 (mean value $pLS.D.) for its metabolite, etretin. Absorption half‐times were 0.86$pL0.04 and 0.55 hrs$pL0.09, respectively. The patients receiving etretin showed a lag‐time of 0.42 hrs$pL0.23 and an absorption half‐time of 0.33 hrs$pL0.28. This suggests that a fraction of etretinate is rapidly hydrolysed to etretin during the absorption process. The mean half‐times of the distributory phases of disposition for etretinate and etretin were about 1 and 1.3 hrs and the apparent terminal half‐lives were 6.57$pL2.09 and 5.52 hrs$pL1.76, respectively. Assuming 40% systemic availability for both drugs the mean apparent volumes of distributions were calculated to be 1.50$pL0.46 and 1.31 l·kg‐1$pL0.53 and mean plasma clearances were 177.8$pL105.8 and 175.9 ml·kg‐1·hr‐1$pL81.4 for etretinate and etretin, respectively. The pharmacokinetic data thus seem to indicate that etretin is absorbed faster after oral ingestion than etretinate, which is partially hydrolysed to etretin, possibly in the gut wall. After distribution about 71% of etretinate and 45% of etretin seems to reside outside of the initial distribution volume in the body.
Dopamine D2Receptor Binding in Striatal Membranes of Rat Lines Selected for Differences in Alcohol‐related Behaviours
Authors: Korpi E. R. , Sinclair J. D. , Malminen O.
Published: March 2009

Abstract:The specific binding of3H‐spiperone to striatal membranes was compared within two pairs of rat lines produced by selective breeding for either differences in voluntary alcohol consumption or for differences in acute ethanol‐induced motor impairment. Although a significant difference was found between the alcohol‐preferring and alcohol‐avoiding rat lines, the estimate for the Bmaxvalue was only slightly lower in naive alcohol‐preferring rats. The small magnitude of the difference suggests it is unimportant for the genetically‐determined differences in alcohol preference. No significant differences were found in the estimates for their Kdvalues. There were no significant differences for either the Bmaxand Kdvalues between the alcohol‐sensitive and alcohol‐insensitive rat lines, which suggests that striatal dopaminergic D2receptors are not involved in the genetically‐determined factors influencing sensitivity to alcohol (and also barbital and lorazepam).
Metabolism in Rats ofp‐Cymene Derivatives: Carvacrol and Thymol
Authors: Austgulen Liv‐Torill , Solheim Einar , Scheline Ronald R.
Published: March 2009

Abstract:The metabolism of carvacrol and thymol in rats was studied using gas chromatographic‐mass spectrometric methods. The urinary excretion of metabolites was rapid. Only very small amounts were excreted after 24 hrs. Although large quantities of carvacrol and, especially, thymol were excreted unchanged (or as their glucuronide and sulphate conjugates), extensive oxidation of the methyl and isopropyl groups also occurred. This resulted in the formation of derivatives of benzyl alcohol and 2‐phenylpropanol and their corresponding carboxylic acids. In contrast, ring hydroxylation of the two phenols was a minor reaction.
Effect of Anticonvulsant Drugs on (35S)t‐Butylbicyclophosphorothionate Bindingin Vitroandex Vivo
Authors: Pitkänen A. , Saano V. , Tuomisto L. , Riekkinen P. J.
Published: March 2009

Abstract:Using several concentrations of eight anticonvulsant drugs in clinical use (carbamazepine, clonazepam, phenytoin, phenobarbital, ethosuximide, primidone, sodium valproate, and D,L‐γ‐vinyl GABA), we studied their abilitiesin vitroto displace (35S)t‐butylbicyclophosphorothionate (35S‐TBPS) from its binding site in a homogenate of rat brain. Thereafter ethosuximide (150 mg/kg), phenobarbital (30 mg/kg), clonazepam (0.3 mg/kg), or phenytoin (100 mg/kg) was injected intraperitoneally into rats for 16–20 days; and the effect of drug administration on35S‐TBPS binding was studied in the cortex and hippocampusex vivo.Phenobarbital (100 μM, P<0.001), ethosuximide (500 μM, P<0.001), and phenytoin (40 μM, P<0.001) decreased the specific35S‐TBPS bindingin vitroby 10–16%. After drug administration of phenobarbital (concentration in plasma 168 μM), the number of binding sites decreased and the binding affinity (P<0.05) in the cortex increased. Other anticonvulsants did not modulate35S‐TBPS bindingin vitroat the concentration analogous to therapeutic plasma levels orex vivoat the dose used. These results suggest that the use of phenobarbital may modulate the TBPS binding site, but the role of the present findings in the anticonvulsant action of phenobarbital needs to be further studied.
The Effect of Diazepam on Nociception in Mice
Authors: Rosland Jan Henrik , Hunskaar Steinar , Hole Kjell
Published: March 2009

Abstract:The antinociceptive properties of diazepam were evaluated in mice, using four different pain tests and different doses of the drug (0.2, 0.5, 1.0 and 2.0 mg/kg). In the tail flick test and the increasing temperature hot plate test there were no effects. In the formalin test reduced licking was observed for the highest dose of diazepam. However, this dose also induced clear sedation possibly causing the reduced licking response. In the constant temperature hot plate test a hyperalgesia was found for all doses tested. This hyperalgesia was not observed in animals adapted to the test apparatus, suggesting that the “hyperalgesic” effect of diazepam may be due to reduced stress analgesia. The serum concentrations of the drug were comparable to therapeutic levels in humans. It was concluded that the sedative and anxiolytic effects of diazepam may influence the results of nociceptive tests, but the drug has probably no effect on nociception in itself.
Studies on Laxatives: Biliary and Urinary Excretion in Rats Given Danthron by Intravenous Infusion or Gastric Intubation
Authors: Sund Reidar Bredo
Published: March 2009

Abstract: Rats were infused with danthron (I) at doses of 0.48, 2.2 and 5.8 μmol/100 g body weight, or given 12 μmol/100 g with gastric tube. TLC of bile and urine demonstrated a number of metabolites, at both administration routes. These included I monosulphate (II) and ‐glucuronide (III), two other phase 2 metabolites which behaved as the corresponding diconjugates, and several phase I metabolites (IV) in conjugated form. IV as a group were estimated by photometry of hydrolysed samples, using I as a reference. Danthron conjugates as a group were determined in such samples by a specific method for I. Moreover, II and III were determined individually in unhydrolysed specimens. Following infusion, about 80% of the danthron conjugates in bile were excreted after 1 hour; the dose fractions found after 5 hours represented about 20%, 30% and 40% at the low, intermediate and high dose level, respectively. The corresponding fractions in urine were 16%, 12% and 10%, giving rise to bile:urine excretion ratios of 1.3, 2.7 and 4.0, respectively. This change in excretion pattern was associated with changes in metabolite muster, which involved a decrease in the balance of IV:I conjugates, as well as an increase in III:II ratio. IV was more abundantly present in bile than in urine, and showed a more sustained excretion than the I conjugates. By intragastric administration, the cumulated excretion (bile+urine) of I conjugates were only 6%, 8% and 5% of dose, in three concecutive 6 hours'periods (0–6, 6–12 and 12–18 hours after dosing). The bile:urine excretion ratios seemed to decrease with time, as did the III:II ratio. Except for some spillover in urine at higher intravenous doses, insignificant fractions of unconjugated I were found in both bile and urine. According to these results, danthron displays a much more complex pharmacokinetic pattern than do diphenylmethane laxatives such as bisacodyl. Clearly, the excretion of phase 2 conjugates of danthron in urine, which previously has been used as an index of I absorption, represents an underestimate of that parameter.
Laxative Potency and Acute Toxicity of Some Anthraquinone Derivatives, Senna Extracts and Fractions of Senna Extracts
Authors: Hietala Pentti , Marvola Martti , Parviainen Tuuli , Lainonen Heli
Published: March 2009

Abstract: This paper investigates the laxative effect and acute toxicity of certain fractions of senna extracts in mice. The same tests were also carried out with several pure anthraquinone derivatives common in senna pods. The results show that the laxative and toxic components of senna pods and senna extracts can be separated. The most potent laxative components, sennosides A+B and Fraction V (relative potencies 1 and 0.9 respectively), have the lowest toxicity (relative intravenous toxicities 1 and <1). Fractions with very low laxative activity (rhein‐8‐glucoside and Fraction IV, relative potencies 0.56 and 0.05) have the highest acute toxicity (relative toxicities 10 and 32 respectively).
Selective D1 and D2 Receptor Manipulation in Cebus Monkeys: Relevance for Dystonia and Dyskinesia in Humans
Authors: Kistrup Kristen , Gerlach Jes
Published: March 2009

Abstract: Selective D1 and D2 dopamine (DA) antagonists and agonists were given to 4 Cebus monkeys who had previously received haloperidol treatment for 4 years. SCH 23390 (a selective D1 antagonist) and raclopride (a selective D2 antagonist) induced identical syndromes consisting of dystonia and oral dyskinesia. Biperiden (an anticholinergic drug) and LY 171555 (a selective D2 agonist) completely antagonized the dystonia and dyskinesia induced by SCH 23390 as well as raclopride. The combined treatment with LY 171555 and SCH 23390 (but not LY 171555 and raclopride) caused pronounced sedation. LY 171555 induced repetitive movements of head, legs and trunk, but no oral dyskinesia. SKF 38393 (a partial D1 agonist) caused slight sedation, minimal oral dyskinesia and a significant reduction in D2 agonist‐induced repetitive movements.
Alkaline Phosphatase Activities Following Repeated Suramin Administration in Some Rat Tissues in Relation to Their Functions
Authors: Akanji Musbau A. , Nlumanze Stella E.
Published: March 2009

Abstract: The effect of repeated administration of suramin, a trypanocide and filariacide, on the level of alkaline phosphatase activity in some rat tissues and organs was investigated. Daily administration of this drug to rats resulted in a very significant increase in enzyme activity in the kidney and small intestine immediately after the first dose. Activity observed in the liver was not affected until after the third dose when the level was increased. In the heart and the large intestine, administration of the drug did not affect the enzyme activity levels throughout the duration of drug administration. These results suggest that repeated suramin administration may result in very large increases in alkaline phosphatase activity in the tissues and organs which are involved in active transport mechanisms.
The Metabolism of 2,5‐Diphenyloxazole (PPO) in Human Lymphocytes and Rat Liver Microsomes
Authors: Ahokas J. T. , Davies C. , Jacobsen N. , Kärki N. T. , Philippides A. , Treston A. M.
Published: March 2009

Abstract:The oxidative metabolism of 2,5‐diphenyloxazole (PPO) is associated with 3‐methylcholanthrene inducible cytochrome P‐450. The major metabolite formed has m/z of 237, corresponding to hydroxylated PPO. All the possible hydroxylated metabolites of PPO were synthesized and characterized, enabling the assignment of a structure for the major metabolite and two minor metabolities. The metabolities are easily extracted and their fluorescence is quantifiable in alkaline medium with a sample fluorescence to blank fluorescence ratio of 400:1. A sensitive HPLC assay of PPO metabolism was also developed. PPO metabolism is readily catalyzed by 3‐methylcholanthrene‐induced rat liver microsomes and strongly inhibited by α‐naphthoflavone, but poorly inhibited by metyrapone or SKF 525A, indicating the involvement of cytochrome P‐448 or P1‐450 in the metabolism of PPO. With human lymphocytes the method has proven to be a good indicator of “aryl hydrocarbon hydroxylase” (AHH) activity, correlating well with AHH assays using benzo(α)pyrene (BP) as a substrate. Both the induced BP and PPO metabolism by human lymphocytes is inhibited by α‐naphthoflavone, but not by metyrapone.
Trichloroethylene and Halothane Inhibit Uptake and Metabolism of 5‐Hydroxytryptamine in Rat Lung Slices
Authors: Hede A. Ragnar , Berglund Bengt G. , Post Claes
Published: March 2009

Abstract:The effect of exposure to organic solvents on uptake and metabolism of 5‐HT was studied in rat lung slices. It was found that under control conditions 5‐HT was both taken up and metabolized to 5‐HIAA. When halothane (35,000 ppm) or trichloroethylene (18,000 ppm) were equilibrated with the incubation medium the uptake of 5‐HT decreased by approximately 50% after 30 min of incubation, and the production of 5‐HIAA was inhibited by approximately 70% and 80%, respectively. The results are consistent with earlier studies using a much more elaborate technique, in which halothane and trichloroethylene were found to depress 5‐HT uptake in isolated perfused rat lungs. Our results demonstrate that the simpler technique employing lung slices can also be used, to investigate factors affecting pulmonary uptake of endogenous amines, and, potentially, the uptake of other compounds as well.
Effects of Indomethacin on Hormonal and Blood Pressure Responses to Captopril in Spontaneously Hypertensive Rats
Authors: Säynävälammi Pekka , Arvola Pertti , Kuismanen Kari , Seppälä Erkki , Nurmi Anna‐Kaisa , Manninen Vesa , Vapaatalo Heikki
Published: March 2009

Abstract: The possible role of vasodilatory prostanoids in the antihypertensive action of captopril was investigated in spontaneously hypertensive rats (SHR). Captopril (100 mg/kg/day for 5 days) decreased systolic blood pressure and increased water consumption, urine excretion and plasma renin activity (PRA). It also enhanced the urinary excretion of the prostacyclin metabolite 6‐keto‐PGF1α, but did not change the excretion of PGE2. Indomethacin (3 mg/kg/day), given both alone and in combination with captopril, reduced markedly the urinary excretions of 6‐keto‐PGF1α and PGE2 but did not alter PRA, compared with corresponding groups without indomethacin. The suppression of prostanoid synthesis caused by indomethacin did not affect the antihypertensive effect of captopril or the basal blood pressure in SHR. Neither did indomethacin influence drinking or urine excretion in SHR not receiving captopril, but it reduced the dipsogenic and diuretic effects of captopril. The results suggest that captopril augments the production of vasodilatory prostacyclin. Yet prostanoids have no significant role in the antihypertensive mechanism of captopril in SHR.
Effects of 3H‐Thymidine on Preimplantation Mouse Embryos in Vitro
Authors: Olsen Wenche Marie , Storeng Ritsa
Published: March 2009

Abstract: The effect of 3H‐thymidine on in vitro development of preimplantation mouse embryos was studied. Two‐cell and 4–8‐cell embryos from B6CBA/F1 mice were continuously exposed to 3H‐thymidine in medium containing 3H‐thymidine in concentrations ranging from 10–500 nCi/ml. The effect of the radioactive precursor on embryo development to the blastocyst stage was studied by morphological observation, counting the blastocyst cell number and measuring 3H‐thymidine incorporation. The continuous presence of 3H‐thymidine significantly inhibited development of 2‐cell and 4–8‐cell embryos to the blastocyst stage. Embryos cultured from the 2‐cell stage were more sensitive to 3H‐thymidine than those exposed from the 4–8‐cell stage. Even in morphologically normal blastocysts the cell number was significantly reduced. A 2 hr pulse of 100 nCi/ml 3H‐thymidine at the blastocyst stage, did not affect the blastocyst formation or the blastocyst cell number and the amount of incorporated 3H‐thymidine was sufficient to provide a reliable quantitation of DNA synthesis during the culture of preimplantation embryos in vitro. Continuous incubation with 3H‐thymidine in order to measure DNA synthesis of preimplantation mouse embryos should be avoided when DNA synthesis is used as a means of evaluating toxic effect of an agent. Adverse radiation effects by 3H‐thymidine on preimplantation mouse embryos during toxicity testing can be avoided by pulse labelling.
Effects of 1,1,1‐Trichloroethane on Synaptosomal Calcium Accumulation in Mouse Brain
Authors: Nilsson Karin B.
Published: March 2009

Abstract:Addition of 1,1,1‐trichloroethane (TCE),in vitroto synaptosomes isolated from the mouse cerebellum and cerebral cortex inhibited the slow phase of K+‐stimulated45Ca2+influx and the net45Ca2+influx (Δk). In the brain stem, however, TCE increased the fast and slow phases of calcium uptake under depolarizing conditions and also Δk. The non‐depolarized calcium influx was not altered by TCE addedin vitro.Two hours after injection of TCE (2.4 g/kg) the calcium accumulation in the presence of high K+was lowered in the cerebellar synaptosomes, while it was increased in brain stem synaptosomes. TCE administeredin vivodid not alter the calcium influx into cerebrocortical synaptosomes nor did it affect the non‐depolarization‐induced45Ca2+influx. Thus, these data indicate that TCE may influence voltage‐dependent calcium channels in mouse brain synaptosomes.
Lack of Effects of Polychlorinated Biphenyls on Testosterone Synthesis in Mice
Authors: Johansson Björn
Published: March 2009

Abstract: Male mice were exposed to two different preparations of PCBs. The pure congener 2,2′,4,4′,5,5′‐hexachlorobi‐phenyl (6‐CB) was given at daily doses of 4, 20, and 40 mg/kg b.wt. during the perinatal or pubertal period. A technical mixture of PCB (Clophen A50®) was administered during puberty at daily doses of 8, 40, 80, 120, and 160 mg/kg b.wt. Treatments were, in the different experiments, carried out every second or third day for three to five weeks. Treatment during puberty was started when the mice were 5 weeks old. The perinatal exposure was started on day 13 of gestation and ended on day 24 post partum. There were no significant differences in the plasma levels of testosterone between the treated mice and the controls after any of the treatments, but there was an increase in the relative testes weights for the animals treated perinatally. No influence on the biosynthesis of testosterone in the testicular interstitial cells in vitro could be demonstrated.
Does Vitamin E Supplementation Modulate in Vivo Arachidonate Metabolism in Human Inflammation?
Authors: Lauritsen Karsten , Laursen Laurits S. , Bukhave Klaus , Rask‐Madsen Jørgen
Published: March 2009

Abstract: To determine whether supplementation with the physiological radical scavenger, vitamin E, would modulate arachidonate metabolism in human inflammation, we performed equilibrium dialysis of rectum in eight patients with active ulcerative colitis confined to the rectum. The patients, all off drug treatment, were supplemented with 1920 IU/day of α‐tocopherol and had rectal dialysis done at entry and after three and 14 days. Luminal concentrations of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), determined by radioimmunoassay in purified dialysates, were significantly raised compared to healthy controls. Supplements caused no change in these levels either at day 4 or 15, although serum‐tocopherol showed a 3‐fold increase. Also disease activity was unaffected. This failure of vitamin E supplementation to suppress the mucosal release of PGE2 and LTB4 in active inflammation does not encourage controlled trials on the effect of oral vitamin E in ulcerative colitis.
The Interaction of Copper (Cu++) with the Erythrocyte Membrane and 2,3‐Dimercaptopropanesulphonate in Vitro: A Source of Activated Oxygen Species
Authors: Aaseth Jan , Ribarov Stefan , Bochev Petyo
Published: March 2009

Abstract: The therapy of copper poisoning and of Wilson's disease with 2,3‐dimercaptopropane‐1‐sulphonate (DMPS) may increase the copper‐induced haemolysis. Some aspects of the mechanism of this effect were investigated. The possible generation of activated oxygen species during the interaction of Cu++ and DMPS was studied using a chemiluminescent method detecting oxygen radicals. It was found that incubation of DMPS with copper ions (free or bond with erythrocyte membranes) is accompanied with generation of oxygen radicals. Activated oxygen species produced via O2‐ are able to increase the haemolytic effects of cupric salts. Hence DMPS treatment in cases of copper poisonings or Wilson's disease may involve risk of side effects on the basis of activated oxygen species generation.
Effect of a Sodium‐Poor Diet on Lithium Clearance at Different Dietary Potassium Contents in Rats
Authors: Thomsen Klaus , Leyssae Paul P.
Published: March 2009

Abstract: In rats on a diet with a sodium content of 300 mmol/kg, lithium is reabsorbed exclusively in the proximal tubules, and lithium clearance (CLi) equals the proximal tubular fluid output (Vprox). In rats on a sodium‐poor diet (5 mmol/kg), lithium is also reabsorbed in the distal nephron and CLi is therefore lower than Vprox. The present paper examines the reduction of CLi in response to a low sodium diet in Brattleboro rats with hereditary diabetes insipidus maintained on different dietary potassium contents. CLi was reduced by about 60 μl/min./100 g body weight in response to a low sodium diet. The absolute reduction in CLi caused by low sodium diet was unaffected by an increase of CLi provoked by administration of potassium with the diet, and it was unaffected by variations of CLi which occurred spontaneously within each group. CLi was accordingly reduced by a constant absolute value rather than by a constant percentage. The reduction of CLi (60 μl/min./100 g body weight) was equal to CLi in the group given a potassium‐poor diet with a normal sodium content. In the low‐sodium and low‐potassium group CLi was reduced to almost zero. Using CLi as a measure of Vprox in the rats on a 300 mmol/kg sodium diet it is concluded that the absolute reduction of CLi in response to a sodium‐poor diet is 1) unaffected by increase of Vprox produced by administration of potassium with the food, 2) unaffected by spontaneous variations of Vprox, and 3) equal to Vprox in rats given a potassium‐poor diet.
Effects of Propiomazine on the EEG Sleep of Normal Subjects
Authors: Almqvist M. , Liljenberg B. , Hetta J. , Rimon R. , Hambert G. , Roos B.‐E.
Published: March 2009

Abstract: The effects of 25 mg propiomazine were examined in ten healthy volunteers in a sleep laboratory setting. A significant decrease in sleep latency and a corresponding decrement in subjectively assessed sleep latency was found during drug treatment. The distribution of the different sleep stages was affected to a relatively small extent. Some evidence for a suppression of REM‐sleep in the early part of the treatment period was found. Based on subjective assessment, the subjects rated their sleep quality as significantly improved during treatment. Ratings of “drowsiness in the morning” were not different during baseline and drug treatment, but there was a significant decrease at withdrawal.
Oral Administration of Codeine in the Presence of Ethanol: A Pharmacokinetic Study in Man
Authors: Bodd Egil , Beylich Kari Mette , Christophersen Asbjørg Solberg , Mørland Jørg
Published: March 2009

Abstract:Three healthy male volunteers were given a codeine (1 mg/kg) solution in the absence and presence of ethanol in a cross‐over designed study. The blood ethanol concentration was kept at approximately 16 mM for 8 hrs. Blood samples were taken at several occasions during the first day after the codeine administration. Urine was sampled during three days. There were no significant differences in the area under serum concentration versus time curve in the absence and presence of ethanol with respect to free codeine, total codeine and total morphine. The fraction of codeine glucuronized in serum (approximately 94%), the maximum serum concentration of free (0.34 μM) and total codeine (6.3 μM), the time to reach the maximum serum concentration values (approximately 65 min.) were also similar in the absence and presence of ethanol. The accumulated percentage of the codeine dose given which was found as codeine and morphine and their conjugates in the urine ranged from 50 to 91 percent in the different subjects. The accumulated percentage of the administered codeine dose found as free morphine in the urine, was significantly lower in the ethanol exposed individuals (0.18$pL0.03%) compared to the controls (0.39$pL0.09%). The percentage of the codeine dose found in the urine in the control situation as free codeine (5.2$pL2.2%) was not statistically different from the amount found in the urine after ethanol treatment (4.3$pL2.0%). The percentage glucuronized morphine (95.3$pL0.4%) and codeine (91.9$pL2.2%) in the urine in the absence of ethanol was similar to glucuronized morphine (95.3$pL2%) and codeine (93.1$pL3%) after ethanol exposure. The results suggest that there is probably no significant biological interaction of ethanol with codeine pharmacokineticsin vivoin humans.
Meptazinol and Pentazocine: Effects on Prolactin, Growth Hormone and Vasopressin Levels in Plasma
Authors: Manner T. , Kanto J. , Scheinin H. , Viinamäki O. , Scheinin M.
Published: March 2009

Abstract:The effects of two partial agonist opioid analgesics, meptazinol (at doses 0.7 and 1.4 mg/kg intravenously) and pentazocine (at doses 0.3 and 0.6 mg/kg), on anterior and posterior pituitary hormone secretion were studied in six normal human volunteers. Both drugs stimulated the secretion of prolactin dose‐dependently, as expected. This effect was seen in all subjects, although two of the six subjects reacted more sensitively to both drugs. Plasma growth hormone concentrations were increased only after the higher dose of meptazinol. This was also seen in all subjects suggesting a spesific pharmacological effect. Vasopression (AVP) in plasma was greatly increased (up to 76 pg/ml) in three of the six subjects after the higher dose of meptazinol, but remained on a low level in the other three and after all other drug doses. The increase in AVP occurred only in those individuals who reported nausea after meptazinol. It was concluded that the augmented AVP release following meptazinol administration was likely to be a non‐specific response induced by nausea and not an effect mediated by opiate receptors.
Pharmacodynamics and Pharmacokinetics of Ethanol, Diazepam and Pentobarbital in Young and Aged Rats
Authors: Guthrie Sally , Cooper Ralph L. , Thurman Ronald , Linnoila Markku
Published: March 2009

Abstract:Sleeping time was measured in groups of old and young rats following the intraperitoneal injection of pentobarbital (39.5 mg·kg‐1), diazepam (30 mg·kg‐1) and ethanol (3 g·kg‐1). Concentrations of pentobarbital, and unbound and total diazepam in serum, and ethanol in breath were quantified; as well as whole brain concentrations of diazepam and N‐demethyldiazepam. Healthy old rats slept significantly longer than young rats after receiving diazepam and ethanol but not pentobarbital. There were no significant differences in serum or whole brain concentrations of diazepam or N‐demethyldiazepam between healthy young and old rats. There were also no changes in the serum pentobarbital or breath ethanol concentrations between the young and old rats. Increases in pharmacologic effect that occur with aging may be caused by alterations in pharmacokinetic parameters or changes at the site of drug action. The cause of an increased pharmacodynamic effect depends upon the specific drug, possibly because these compounds affect the same receptorionophore complex at different sites.
Retention and Subsequent Liberation of Glyceryl Trinitrate in Organ Baths Influences the Relaxation of Bovine Mesenteric Arteries Contracted by Various Agents
Authors: Ahlner Johan , Axelsson Krister L. , Ljusegren Marie Ekstam , Norlander Björn , Andersson Rolf G. G.
Published: March 2009

Abstract: The present study compares the relaxant effect of glyceryl trinitrate (GTN) on isolated bovine mesenteric artery in commonly used organ baths made of glass and in disposable vials made of polyethylene, a material known to be inert to GTN. It is shown that the EC50‐value for the GTN‐induced relaxation is about 1000‐fold lower when polyethylene vials are used. The study also shows that the reason for this is that the materials previously used in the experimental equipment retain and subsequently liberate GTN at re‐use. In organ baths of glass with holders of acrylics, GTN concentrations of about 20 nM were found during equilibration, i.e. before start of the experiment. The vessel specimens become partly tolerant during equilibration in such organ baths and thus the vessels are less sensitive to GTN. The findings may explain the discrepancy between previous in vitro and in vivo studies. Low concentrations known to be effective in vivo have not been demonstrated to have a relaxant effect in earlier in vitro studies.