bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Certain Chelating Agents on Egress of Cadmium from Cultured Epithelial Cells Containing High Amounts of Metallothionein: A Screening of Cd‐Releasing and Toxic Effects
Authors: Bakka Arne , Aaseth Jan , Rugstad Hans Erik
Published: July 2010

Abstract:Cell cultures have been used to study the effect of 6 different metal chelating compounds on the efflux of Cadmium (Cd) from the cells and on cell growth. The cells had previously been made resistant to high levels of Cd (100 μmol/1) in the medium. They contain large amounts of intracellular Cd (40–50 nmol Cd/mg cell protein), the main part of which is bound to cytoplasmic metallothionein. Among the different monothiol and dithiol compounds tested are some old, well‐known and to some extent therapeutically tried substances, i.e. 2,3‐dimercapto‐1‐propanol (BAL), D‐penicillamine (PA), N‐acetyl‐DL‐penicillamine (NAPA) and some newer metal chelators, i.e. 2,3‐dimercaptopropane‐1‐sulphonate (BAL‐Sulph), mercaptosuccinic acid (MSA) and meso‐2,3‐dimercaptosuccinic acid (DMSA). The three latter ones all showed better effect on the egress of Cd than PA and NAPA and less toxic effect than BAL on an equimolar basis. All the agents tested increased the efflux of Cd from metallothionein‐containing cell cultures which seem to be justified as a test system for primary screening of effect and toxicity of new chelators.
Stimulus Pattern and Tolerance Development. Exposure of Rats to Alternating Light/Darkness Patternsin Vivoand Pilocarpine Sensitivityin Vitroof the Iris Sphincter
Authors: Claesson‐Backlund Helen
Published: July 2010

Abstract:Pigmented rats were kept under different light/darkness patterns for 5–12 days. The response of the iris sphincter in enucleated eyes was tested with pilocarpine as a standard stimulus. The eyes were either decorneated or intact. The maximum response (no subsensitivity) was obtained after continuous darkness and the minimum (maximum subsensitivity) after continuous light. Six hours of light and one block of 18 hours of darkness per day caused distinct subsensitivity, but less than if the light was interrupted by six 3‐hour darkness periods. Further subdivision of the light into twelve 30‐min. periods made no difference. One 18‐hour block of light followed by 6 hours of darkness caused less subsensitivity than continuous light. Subdividing the darkness into six 1‐hour periods made no significant difference.
Convulsive Effect of Theophylline in Conscious and Anaesthetized Guinea‐pigs
Authors: Persson Carl G.A. , Erjefält Ingrid
Published: July 2010

Abstract:In urethane‐anaesthetized guinea‐pigs, the effect of theophylline (theo) on heart rate, arterial blood pressure, respiration rate and limb movements were recorded. Continuous intravenous infusion of theo initially increased the respiratory and heart rates and lowered the arterial blood pressure. After infusion of about 50 mg/kg of theo, the cardiovascular effects reached a maximum and were then only slightly changed until the terminal stage. A tonic stretching of the limbs (at 155 ± 15 mg/kg) preceded generalized seizures of clonic tonic convulsions which were recorded after infusion of 367 ± 25 mg/kg of theo. At this stage, respiration was highly irregular. PaO2started to fall and PaCO2to rise, while a plasma acidosis developed rapidly. The convulsions progressed in frequency and intensity and were terminally associated with respiratory and cardiovascular collapse. The convulsive effects of theophylline were similar to those observed in conscious guinea‐pigs after 250 mg/kg of theo orally. The present findings agree with the view that the convulsive effect is a primary life‐threatening action of theophylline. The method described may be of use in the search for new, less toxic xanthine drugs.
Effects of Tartrazine on Different Contractile Stimuli in Guinea Pig Tracheal Muscle
Authors: Hedman Susan E. , Andersson Rolf G. G.
Published: July 2010

Abstract:Tracheal smooth muscle obtained from ovalbumin‐sensitized guinea pigs contracted with micromolar concentrations of tartrazine and indomethacin. The contractions were slightly reduced by clemastine, but were completely blocked by the SRS‐A antagonist FPL 55712. Arylsulfatase B, which is an enzyme that inactivates SRS‐A, also abolished the contractions induced by tartrazine. Contractions induced by carbacholine, histamine, egg albumin and arachidonic acid were slightly reduced by indomethacin and tartrazine. Tartrazine like indomethacin inhibited the generation of thromboxanes from human platelets. We suggest that SRS‐A plays an important role in the immediate hypersensitivity reactions of tartrazine and indomethacin in guinea pig trachea.
Exploratory and Socio‐Sexual Behaviour in the Male Laboratory Rat: A Methodological Approach for the Investigation of Drug Action
Authors: Meyerson B. J. , Höglund A. U.
Published: July 2010

Abstract: There is an increasing demand for appropriate methods for analysing the pharmacological and toxicological action of chemical agents on behavioural patterns. The present study describes a non‐instrumental approach to the study of exploratory and socio‐sexual behaviours in the laboratory male rat. The behaviours were differentiated in terms of latency of onset, incidence, frequency and duration. Castrated and intact males were tested under three defined test situations. One test was focused on exploratory behaviour and two tests in which the male encountered an oestrous female or a castrated male were set up to study social and sexual behaviours. A multivariate statistical method was used to analyse differences in the behavioural profiles observed in the different tests. The data show that simultaneous recording of several spontaneous behaviours may be a useful technique for investigating how a compound influences behavioural processes.
Effect of Copper on the Uptake and Release of Monoamines in Rat Brain Synaptosomes
Authors: Komulainen Hannu , Tuomisto Jouko
Published: July 2010

Abstract:Effect of Cu2+(as CuCl2) on the high affinity uptake and spontaneous release of tritiated noradrenaline (NA), dopamine (DA) and 5‐hydroxytryptamine (5‐HT) were studiedin vitroin rat cortical, striatal and hypothalamic synaptosomes, respectively. Cu2+inhibited noncompetitively DA and 5‐HT uptake and the inhibition was dependent on incubation time; the IC50 values (2 min. incubation) were 1.0 μM (DA) and 6.6 μM (5‐HT). Preincubation of synaptosomes with Cu2+(5 min.) further potentiated the inhibition. NA uptake was also inhibited at low Cu2+concentrations (IC50 0.8 μM) but at concentrations higher than 10 μM, Cu2+increased the3H‐NA associated with synaptosomes both at 37° and 0°. Preincubation, in contrast to its effect on DA and 5‐HT uptake, decreased inhibitory potency of Cu2+for NA uptake. Cu2+increased the release of these amines over spontaneous release from preloaded synaptosomes in a time and concentration dependent fashion, that of DA more easily than that of NA or 5‐HT. Thus Cu2+decreased the net accumulation of monoamines in synaptosomes possibly by inhibiting their reuptake and increasing their efflux. At high concentrations Cu2+increased the accumulation of NA in/on synaptosomes possibly by some passive process, e.g. chelation and/or increased diffusion. It is possible that Cu2+, at high concentrations in cases such as poisoning or Wilson's disease, could affect the functions of the central nervous system by disturbing the neurotransmission at monoaminergic nerve terminals.
Interference of Methyl Mercury with Monoamine Uptake and Release in Rat Brain Synaptosomes
Authors: Komulainen Hannu , Tuomisto Jouko
Published: July 2010

Abstract:Interference of methyl mercury (Met‐Hg), a known neurotoxin, with the high affinity uptake and the release of tritiated dopamine (DA), noradrenaline (NA) and serotonin (5‐HT) was studiedin vitroin rat striatal, cortical and hypothalamic synaptosomes respectively. Met‐Hg proved to be a potent inhibitor of uptake; the IC50's were 2.5 μM (DA), 3.2 μM (NA) and 3.4 μM (5‐HT) in 2 min. incubations. The uptake of NA was slightly inhibited already at 0.1–1 μM Met‐Hg whereas DA and 5‐HT were not. The inhibition was rapid, already after 1 min. exposure to 3 μM Met‐Hg the uptake was inhibited totally. The kinetic pattern of the inhibition of DA uptake best agreed with the non‐competitive type. The spontaneous release of monoamines from preloaded synaptosomes was also potently stimulated and was dependent on Met‐Hg concentration. The sensitivity decreased in the order of DA>5‐HT>NA. The apparent inhibition of uptake is probably partly due to the release of the transmitter amine just taken up. Chelation might also contribute to the inhibition of NA and DA uptake. The detailed mechanisms of these phenomena remain to be studied but they may explain some of the direct CNS effects of Met‐Hg.
Biotransformation of Xenobiotics in Isolated Dog Hepatocytes
Authors: Bolcsfoldi G. , Johansson M. , Andersson B. , Moldeus P.
Published: July 2010

Abstract:A method for the preparation of dog hepatocytes in a viable state by perfusion of the liver with collagenase is described. Dog hepatocytes are compared with rat hepatocytes with regard to cell size, protein and cytochrome P‐450 content, rate of biotransformation of bromobenzene, harmine and paracetamol and glutathione biosynthesis,in vitro.Quantitative differences in these parameters between dog and rat hepatocytes are reported.
Effect of Cocaine and Corticosterone on the Metabolism of3H‐Noradrenaline Released from Rabbit Isolated Aorta and Adventitia
Authors: Schrold Jørgen , Nedergaard Ove A.
Published: July 2010

Abstract:The effect of cocaine and corticosterone (neuronal and extraneuronal uptake inhibitors, respectively) on the metabolism of3H‐noradrenaline (3H‐NA) released spontaneuosly or by electrical‐field stimulation was studied in the rabbit isolated aorta and tunica adventitia preloaded with3H‐NA. The spontaneous outflow of tritium from untreated aorta consisted of3H‐NA (25%);3H‐3,4‐dihydroxyphenylglycol (3H‐DOPEG; 24%);3H‐3,4‐dihydroxymandelic acid (3H‐DOMA; 8%);3H‐O‐methylated plus deaminated compounds (3H‐OMDA; 45%); and3H‐normetanephrine (3H‐NMN; 1%). The percentage distribution of3H‐NA and its3H‐metabolites in this outflow was not altered by either cocaine (3 × 10−5M), corticosterone (4 × 10−5M), or cocaine (3 × 10−5M) + corticosterone (4 × 10−5M). The spontaneous3H‐outflow from untreated tunica adventitia did not differ from that of aorta. Cocaine (3 × 10−5M) + corticosterone (4 × 10−5M) did not alter the composition of3H‐NA and its3H‐metabolites in the spontaneous outflow from adventitia. The stimulation‐evoked3H‐overflow from untreated rabbit aorta preloaded with3H‐NA consisted of3H‐NA (40%);3H‐DOPEG (15%);3H‐DOMA (2%);3H‐OMDA (50%); and3H‐NMN (3%). Cocaine (3 × 10−5M) decreased the percentage recovered as3H‐DOPEG, increased3H‐NMN and had no effect on the other3H‐metabolites. Corticosterone (4 × 10−5M) had no effect on the percentage distribution of3H‐NA and its3H‐metabolites. Cocaine (3 × 10−5M) + corticosterone (4 × 10−5M) increased3H‐NA, decreased3H‐DOPEG and had no effect on the percentage distribution of the other3H‐metabolites. In the case of adventitia, cocaine (3 × 10−5M) + corticosterone (4 × 10−5M) only decreased the percentage recovered as3H‐DOPEG, without any significant effect on3H‐NA and its other3H‐metabolites. It is concluded that inhibition of neuronal plus extraneuronal uptake of H‐NA by cocaine plus corticosterone, respectively does not fully prevent metabolism of3H‐NA released either spontaneously or by electrical‐field stimulation.
The Tissue‐Disposition of Gentamicin in Rats
Authors: Larsson Bengt , Nilsson Monica , Tjälve Hans
Published: July 2010

Abstract:The tissue disposition of14C‐gentamicin was studied in young rats after a single‐dose administration by autoradiographic techniques. The autoradiograms showed a high accumulation of the substance in non‐parenchymateous tissues such as cartilages and connective tissues and a strong uptake in the kidney cortex. Thein vivobound substance was displaced from the cartilage at incubations in cation‐containing solutions, indicating an ionic binding of the polycationic gentamicin to negatively charged groups in the cartilage (probably carboxyl and sulphate groups of chondroitin sulphate). In the inner ear a localization of the substance was found in the membraneous walls of the chochlea and, at short survival intervals, in the perilymph, whereas the radioactivity in the endolymph was low. Studiesin vitroshowed an ionic binding of gentamicin to cartilage and in addition to several other tissues, such as the lymphomyeloid system, the gastrointestinal mucosa, the exocrine pancreas, salivary glands, and most prominent, the pigmented tissues. A strongin vitrobinding of gentamicin to pigment from beef eyes was also shown. The potential binding sites in the latter tissues are localized intracellularly and are therefore apparently unattainable for the charged hydrophilic gentamicin moleculein vivo.
An Early Sign of Xylene Effect on Human Equilibrium
Authors: Savolainen Kai , Riihimäki Vesa
Published: July 2010

Abstract: The effects of m‐xylene on the equilibrium system of 22 healthy males were studied during inhalation exposure to stable and fluctuating xylene concentrations of 2.6–16.4 μmol/1 (64–400 p.p.m.), at rest and during exercise, for 6 hours daily over 5 successive days. The exposures were continued after a 2‐day weekend for an additional 1–3 days. A strain gauge transducer platform was used to record the body sway of the subjects with their eyes closed and open. The eyes closed/eyes open ratio, indicating the relative significance of vestibular (equilibrium) involvement by xylene, was calculated. An increased eyes closed/eyes open ratio seemed to be an early effect of xylene (blood xylene 20–30 μmol/1) on the vestibular (equilibrium) system to which the naive subjects soon became adapted or tolerant. Only fluctuating xylene concentrations in the air when the subjects were at rest or exercising could repeatedly induce an increase in the ratio, a phenomenon demonstrating the importance of rapidly increasing blood xylene levels. Probably due to adaptation or tolerance, no dose‐response relationships between the increase in the eyes closed/eyes open ratio and blood xylene concentrations was found.
Synthesis and Solubility of Collagen in Rats during Recovery after High‐dose Cyclophosphamide Administration
Authors: Wie Henrik , Beck Eva Imislund
Published: July 2010

Abstract: The metabolism of collagen and mineral was studied during a nine‐day postmedicational period in young, male rats receiving high‐dose intraperitoneal cyclophosphamide treatment every second day for 12 days. Two days after ending medication the white blood cell counts (WBC) were reduced by about 70%. Both synthesis and solubility of collagen were suppressed by the present medication 2 days after termination of treatment. This suppression continued throughout the 9‐day postmedicational period in bones, whereas in connective tissue of porous, ceramic implants both total collagen and the amount of salt soluble collagen regained normal values 9 days after cessation of treatment. Increased mineralization was found 2 days after ending medication and this high degree of mineralization persisted during the postmedicational period studied. Serum albumin levels were reduced and no increases were detected during the postmedicational period. The suggestion is made that the general protein synthesis is affected by high‐dose cyclophosphamide administration.
A New β2‐Adrenoceptor Agonist with α1‐Adrenoceptor Blocking Properties
Authors: Olsson O. A. T. , Ahlquist B. , Gustafsson B.
Published: July 2010

Abstract:The phenylethanolamine D2343 exhibits a dualistic adrenoceptormediated effect, i.e. a β‐agonistic effect combined with an α‐antagonistic one. Tracheal smooth muscles and heart preparations were used to gauge the agonistic effect on adrenergic β‐receptors. Rabbit aorta and rat vas deferens were used to determine the α‐adrenoceptor blocking activity. The β‐adrenoceptor activity of D2343 was classified as β2‐type with about the same efficacy as the β2‐selective terbutaline on tracheal muscle. The effect on isolated heart preparations was greater than that produced by terbutaline. The α‐receptor blocking capacity was directed against the α1‐receptor type and was of nearly the same potency as for phentolamine.
Changes in Carbohydrate Metabolism in Various Organs of the Snail,Lymnaea acuminatafollowing Exposure to Trichlorfon
Authors: Mahendru V. K. , Agarwal R. A.
Published: July 2010

Abstract:Several aspects of carbohydrate metabolism following 24 hr and 48 hr treatment with 10 and 20 mg/l of trichlorfon, were studied in hepatopancreas, mantle, intestine and foot of the snail,Lymnaea acuminata.Following treatment with the pesticide, the rate of oxygen consumption and concentration of glycogen were reduced, while the levels of lactic acid and reducing sugars were enhanced. Withdrawal of pesticide for 7 days following trichlorfon treatment (10 mg/l for 48 hrs) could not reverse these changes.
Guanine N7‐Alkylation in Mice in Vivo by Metrifonate – Discussion of Possible Genotoxic Risk in Mammals
Authors: Dedek Wolfgang
Published: July 2010

Following intraperitoneal administration to male mice (strain AB Jena/Halle) of 14CH3‐labelled metrifonate, 22 Ci/mol, in dosages of 0.48, 0.40 and 0.065 mmol/kg, DNA from liver and kidneys was analysed for 14C in N‐7 methylguanine (7‐MeG). The extent of methylation in liver was found to be maximal at 6 hrs after injection in amounts of 6–8 and 0.8 μ mol 7‐MeG/mol guanine for the high and the low dose, corresponding to a covalent binding index CB14–5. The half‐life of excretion of 7‐MeG was 5 hrs for the high and 15 hrs for the low dose. The extent of methylation at 0–6 of guanine was estimated to be around 0.002–0.01 μmol 0–6 MeG/mol guanine. Data from references concerning methyl methanesulfonate and dimethyl sulfate are compared with those of metrifonate and the genotoxic response of methylating and non‐methylating metabolites is discussed.
Cultivation of Schistosomes for Chemotherapeutic Studies
Authors: Frandsen Flemming
Published: July 2010

Abstract The routine maintenance and mass production of Schistosoma mansoni and S. haematobium for chemotherapeutic trials or other kind of studies involving mice infected with schistosomes or adult mature schistosomes, is described.
Effect of Propranolol on Myocardial Cell Necroses and Blood Levels of Catecholamines in Pigs Subjected to Stress
Authors: Häggendal J. , Johansson G. , Jönsson L. , Thorén‐Tolling K.
Published: July 2010

Abstract:The degree of myocardial cell necroses in pigs exposed to stress induced by a myorelaxant (succinylcholine) for about 12 min. was investigated. The β‐adrenoceptor blocker propranolol was given in varying doses prior to the induced stress. The degree of necroses in these pigs was evaluated according to a point scale, ranging from 0 to 6 points, and compared with the changes found in untreated controls following stress. The blood levels of noradrenaline and adrenaline were assayed before, during, and immediately after the period of stress. No protective effect of propranolol on the cardiac lesions was found when the drug was administered intravenously in a single dose of either 1 mg or 3 mg per kg. During the period of stress the blood levels of noradrenaline were high, indicating a high degree of activity in the sympatho‐adrenal system. Propranolol in a single dose of 10 mg per kg intravenously reduced the number and size of heart lesions, while the blood levels of the catecholamines were lower under stress than after administration of 1 and 3 mg propranolol. After oral treatment with propranolol, 120 mg three times a day for 6 or 7 days, an almost complete absence of heart cell necrosis after the stress was obtained. The activity of the sympatho‐adrenal system was elevated, as reflected by the high blood levels of catecholamines. The results indicate that stress‐induced heart cell necrosis is mediated via the activity of the sympatho‐adrenal system. The difference between a single and repeated doses of propranolol in protecting the heart suggests a complex ation of the adrenergic β‐receptor blocker.
Interaction between Drug Acetylation and Ethanol, Acetate, Pyruvate, Citrate, and L(minus;)Carnitine in Isolated Rat Liver Parenchymal Cells
Authors: Olsen Harald
Published: July 2010

Abstract:The actylation of sulfanilamide and procainamide in suspensions of isolated rat parenchymal cells was studied in absence and presence of ethanol (33 mM), acetate (0.5–5 mM), citrate (4 mM), pyruvate (4 mM), and L(minus;)carnitine (2 mM). Ethanol treatment enhanced the sulfanilamide acetylation whereas the acetylation of procainamide was considered to be unchanged. Acetate (1–5 mM), citrate, and pyruvate treatment enhanced the acetylation of both sulfanilamide and procainamide. Acetate (4 mM) increased both Kmand Vmaxof both sulfanilamide and procainamide acetylation. Combined treatment with L(minus;)carnitine and either acetate, pyruvate, or citrate enhanced the acetylation rate of sulfanilamide more than acetate, pyruvate, or citrate, respectively alone. In cell suspensions treated with L(minus;)carnitine and acetate or pyruvate, the acetylation kinetics of sulfanilamide changed from zero‐to apparent first‐order. With procainamide as test drug, a further increase of the acetylation rate was found when L(minus;)carnitine was added to citrate or pyruvate. Acetyl‐CoA increased the rate of sulfanilamide acetylation in rat liver homogenates in a dose dependent manner.
Increase in the Penetration of Tracer Compounds into the Rat Brain during 2‐Methyl‐4‐Chlorophenoxyacetic Acid (MCPA) Intoxication
Authors: Elo Heikki A. , Ylitalo Pauli , Kyöttilä Jaana , Hervonen Heikki
Published: July 2010

Abstract: The penetration of different intravenous tracer molecules such as 14C‐labelled 2‐methyl‐4‐chlorophenoxyacetic acid (14C‐MCPA), 14C‐p‐aminobenzoic acid (14C‐PABA), 14C‐sucrose, 14C‐antipyrine and iodinated (125I) human albumin (125I‐HA) into the brain and cerebrospinal fluid (CSF) was studied in MCPA‐intoxicated and control rats. Toxic subcutaneous doses of sodium salt of MCPA (200–500 mg/kg) increased highly the brain/plasma and CSF/plasma ratios of 14C‐MCPA and 14C‐PABA, as compared to the muscle/plasma ratio. Probenecid (200 mg/kg) did not affect the cerebral MCPA concentration in the intoxicated animals. The tissue/plasma ratios of 14C‐sucrose, 14C‐antipyrine and 125I‐HA were also increased in the brain and CSF of intoxicated animals, but the increases were less pronounced than those of 14C‐MCPA or 14C‐PABA. The results indicate that MCPA intoxication caused a selective damage of the blood‐brain barrier in the brain areas studied.
The Mode of Antiarrhythmic Action of Melperone
Authors: Platou Eivind S. , Refsum Helge , Myhre Eivind S. P. , Amlie Jan P. , Landmark Knud
Published: July 2010

Abstract:We studied the mode of antiarrhythmic action of melperone by His bundle electrography combined with programmed electrical stimulation in 21 pentobarbital anaesthetized dogs. Melperone alone (0.5 to 12.5 mg/kg) as well as melperone after sympathetic and parasympathetic blockade caused a dose‐dependent increase in the ventricular and, even more, the atrial effective refractory period without affecting atrial and ventricular conduction times. Melperone shortened the atrioventricular nodal conduction time regardless of sympathetic and parasympathetic blockade. We conclude that the antiarrhythmic effect of melperone is most likely primarily due to adirectclass III antiarrhythmic action.
Renal Glucuronidation of Morphine in the Human Foetus
Authors: Pacifici Gian Maria , Rane Anders
Published: July 2010

Abstract:The glucuronidation of morphine was investigated in kidney microsomes from human foetuses. This reaction was found to be catalyzed in all specimens investigated and the UDP‐glucuronyltransferase activities varied between 0.18 and 0.30 nmol per min. per mg microsomal protein. Intraindividual comparisons with the hepatic glucuronidation rates revealed the renal enzyme rate to be about 50 percent of the hepatic. Oxazepam, and to a lesser extent salicylamide, inhibited the glucuronidation of morphine in kidney microsomes in similarity to what previously was shown in human foetal liver microsomes.
Contractile Effects of Some Polypeptides on the Isolated Urinary Bladder of Guinea‐pig, Rabbit, and Rat
Authors: Sjögren Christer , Andersson Karl‐Erik , Husted Steen
Published: July 2010

Abstract:In isolated detrusor from guinea‐pigs and rats substance P (SP) induced concentration‐dependent phasic contractions. Rabbit detrusor strips responded to SP with an initial phasic and an ensuing tonic contraction. The concentration‐response curve to SP in this preparation had a biphasic appearance. Eledoisin (E) caused contractile responses similar to those of SP when tested on the guinea‐pig detrusor. Somatostatin was tested on the rabbit urinary bladder; it caused a concentration‐dependent rise in basal tone, but no phasic contraction. The responses to SP and E were not affected by tetrodotoxin or physostigmine. They were only partly inhibited by high concentrations of atropine and the anticholinergic drug PR 197. Noradrenaline and isoprenaline caused a concentration‐dependent inhibition of the peptide induced responses in guinea‐pig bladder; at high concentrations of the amines this inhibition was almost complete. Indomethacin did not affect the SP induced contractions in the guinea‐pig bladder, reduced the responses in the rabbit detrusor, but increased them in the rat bladder. Contractions elicited by SP and E were rapidly diminished or abolished after 30 min. treatment in a calcium‐free medium. The responses were also inhibited by the calcium antagonist nifedipine. In guinea‐pig preparations depolarized by potassium (127 mM) both SP and E caused a contractile response approximately 20% of that obtained in normal Tyrode solution. It is concluded that SP and E cause contraction of detrusor by a direct effect on the smooth muscle cells, and that this response is dependent on the extracellular calcium concentration. Prostaglandins may be involved in the SP‐induced response of the rabbit detrusor.
Excretion of Methyl Mercury in Rat Bile: The Effect of Thioctic Acid, Thionalide, Hexadecyl‐ and Octadecylmercaptoacetate
Authors: Refsvik Tor
Published: July 2010

Abstract: Thioctic acid markedly increases the sulfhydryl and sulphide content of bile. This probably reflects the reduction of thioctic acid in the liver, followed by biliary excretion of a reduced derivative. The total biliary excretion of methyl mercury was not increased. Thionalide markedly inhibits biliary excretion of methyl mercury. Simultaneously, the sulfhydryl and sulphide content of bile decreases. This is probably caused by the conjugation of thionalide to glutathione in the liver, thereby blocking the biliary excretion of methyl mercury. Hexadecylmercaptoacetate increases the biliary content of methyl mercury moderately after a temporary decrease, whereas biliary sulfhydryl and sulphide concentrations were unchanged. Octadecylmercaptoacetate does not change the biliary content of methyl mercury, sulfhydryl and sulphides significantly. Smaller parts of hexadecylmercaptoacetate, octadecylmercaptoacetate and thionalide seemed to be excreted as such in bile. These results indicate that methyl mercury cannot be transported from liver to bile as complexed to the sulphides thioctic acid, thionalide, hexa‐ and octadecylmercaptoacetate.
Comparison of Atropine and Dexetimide in Treatment of Intoxications by Selected Organophosphates
Authors: Lüllmann Heinz , Schmaus Helga , Staemmler Cornelia , Ziegler Albrecht
Published: July 2010

Abstract:Mice and guinea pigs were intoxicated by three different organophosphates: DFP, paraoxon, and OMPA. After onset of intoxication the animals were treated by either a mixture of atropine plus obidoxim or dexetimide plus obidoxim. The combination of dexetimide plus reactivator proved to be superior to the combination of atropine plus reactivator in case of DFP intoxication. In guinea pig the LD50 of DFP could be increased from about 20 to 1300 μm/kg b.wt. by dexetimide plus obidoxim when applied after the onset of intoxication. Concerning the paraoxon intoxication both antidote mixtures were found to be equally potent, whereas the purely peripheral intoxication induced by OMPA could only be influenced to a minor degree. The tissue distribution of atropine and dexetimide differs markedly, dexetimide being accumulated faster and to a higher degree. Thus the higher penetration rate of dexetimide into the central nervous system is considered to be the reason of its superiority in the treatment of an organophosphate intoxication of rapid onset.
Renal Clearance of Fluoride in a Steady State Condition in Man: Influence of Urinary Flow and pH Changes by Diet
Authors: Ekstrand J. , Spak C. J. , Ehrnebo M.
Published: July 2010

Abstract: In order to study fluoride renal clearance, four subjects were given 3 mg fluoride as sodium fluoride tablets every 6 hrs for 60 hrs during two separate periods – during production of acid urine induced by a protein rich diet and during production of alkaline urine obtained by giving a vegetarian diet. Plasma and urine were collected every third hour for 72 hours during each experiment. In the protein rich diet period urinary pH was significantly lower than when the subjects were maintained on the vegetarian diet. Lower urinary output of fluoride during the protein rich diet experiment was recorded, however, the difference was not significant. Plasma fluoride at steady state was almost the same during both experiments. Renal fluoride clearance was significantly correlated to urinary pH in both types of experiments. When renal fluoride clearance was plotted versus urinary flow, the correlation was only significant during alkaline conditions. The average renal clearance was not significantly different between the two sets of experiments. It may be concluded, that pH and diuresis both influences fluoride renal clearance. Moreover, the results suggests that dietary components as such, influence renal clearance of fluoride in some way or another.
Arachidonate Metabolism is Changed by Dipyridamole in Guinea Pig Isolated Lungs
Authors: Uotila Pekka
Published: July 2010

Abstract: Fifty nmol of 14C‐arachidonic acid was injected into the pulmonary circulation of guinea pig isolated lungs and the metabolites were analysed from the non‐recirculating perfusion effluent. The main metabolites in the effluent were thromboxane B2 (TxB2), 6‐keto‐PGF1α, a metabolite group migrating on TLC plate near to 15‐keto‐PGE2 and a group of two metabolites (probably 12L‐hydroperoxy‐ and 12L‐hydroxy‐5,8,10,14‐eicosatetraenoic acids). Pulmonary infusion of dipyridamole (20 μM) increased the amount of TxB2 in the perfusion effluent. The amounts of other metabolites were unchanged. 2, 20 or 100 μM of dipyridamole had no effect in vitro on the activity of NAD+‐dependent 15‐hydroxyprostaglandin dehydrogenase in the 100,000Xg supernatant fraction of guinea pig lungs.
Penicillin Toxicity in Isolated Rat Hepatocytes Revealed by Decreased Incorporation of Valine into Proteins
Authors: Vonen Barthold , Mørland Jørg
Published: July 2010

Abstract:Rat liver parenchymal cells were isolated from normal and barbiturate pretreated rats. Cells from untreated animals were exposed to penicillin over a concentration range from 0.14 mM to 14.0 mM (50–5000 μg/ml). An inhibition of the incorporation of14C valine into stationary and medium proteins, ranging from 23% at 0.28 mM to 90% at 14.0 mM, was observed. The effect of a single dose penicillin (1.4 mM) on protein incorporation, enzyme leakage and viability was compared to the effect of paracetamol (6.6 mM) and tertiary butanol (10.9 mM). In these concentrations paracetamol and penicillin both inhibited the incorporation of valine into cell and medium protein in hepatocytes from untreated rats. Tertiary butanol showed no such effect. No drug affected the viability or the leakage of enzymes from the hepatocytes. In cells from barbiturate treated animals both paracetamol, penicillin and tertiary butanol had a significant inhibitory effect on the incorporation of radioactive labelled precursor into cell and medium proteins, but no effect on the leakage of enzymes or viability. The ratio between labelled medium and cell proteins was 31% lower in suspensions of control cells from barbiturate treated animals than in cells from untreated rats. It was concluded that penicillin may exert marked effects on protein metabolism in the frequently used isolated rat hepatocyte system, esspecially if the drug concentration well exceeds the usual cell culture concentration of 30–60 μg/ml.
Cytotoxic Effects of N‐Hydroxyparacetamol in Suspensions of Isolated Rat Hepatocytes
Authors: Holme Jørn A. , Wirth Peter J. , Dybing Erik , Thorgeirsson Snorri S.
Published: July 2010

Abstract:The cytotoxicity of N‐hydroxyparacetamol (N‐OH‐pHAA), a postulated proximate metabolite of the hepatotoxic and nephrotoxic analgesic paracetamol, was studied in suspensions of hepatocytes isolated by collagen‐perfusion of livers of male rats. Incubation of cells with 0.25–2.0 mM N‐OH‐pHAA led after 3–5 hours to increased cell permeability measured by increased trypan blue uptake, increased NADH penetration or leakage of prelabelled51Cr. N‐OH‐pHAA rapidly depleted cellular glutathione, 16% of initial levels were seen after 30 min. incubation.3H‐N‐OH‐pHAA bound covalently to cellular proteins in a time‐ and concentration‐dependent manner, considerably higher binding rates were seen with boiled cells compared to intact cells. Pretreatment of animals with the cytochrome P‐450 inducer phenobarbital did not affect N‐OH‐pHAA cytotoxicity or covalent binding, whereas the cytochrome P‐450 inhibitor metyrapone inhibited both cytotoxicity and binding. Lipid peroxidation in hepatocytes could be seen as a late event after a limited range of N‐OH‐pHAA concentrations. In contrast, lipid peroxidation was an early event in cells exposed to carbon tetrachloride. A minimal exposure time of 30 min. of the hepatocytes to N‐OH‐pHAA was sufficient to elicit cellular damage occurring after 3–5 hours.
Modulation of N‐Hydroxyparacetamol Cytotoxicity in Suspensions of Isolated Rat Hepatocytes
Authors: Holme Jørn A. , Wirth Peter J. , Dybing Erik , Thorgeirsson Snorri S.
Published: July 2010

Abstract:The effect of inhibitors of toxicity of N‐hydroxyparacetamol(N‐OH‐pHAA), a postulated proximate metabolite of paracetamol, was studied in isolated rat hepatocytes. Additions of ascorbate, menadione, thiol‐containing amino acids and glutathione (GSH) led to an increased stability of N‐OH‐pHAA, reduced the covalent binding of N‐OH‐pHAA to cellular protein and decreased GSH depletion caused by N‐OH‐pHAA. Two to three hours elapsed after a 30 min. exposure of the cells to N‐OH‐pHAA before the cells responded with increased cell permeability. Ascorbate, acetylcysteine, GSH and promethazine were capable of inhibiting this second phase of N‐OH‐pHAA cytotoxicity in addition to their effects during the initial exposure phase. In contrast, the anti‐oxidant tocopherole and phenacetin were only effective during the second phase. Increasing the incubation medium pH during the second phase of N‐OH‐pHAA mediated cellular damage resulted in decreases in cytotoxicity. Lipid peroxidation, as measured by accumulation of thiobarbituric acid reactive metabolites, did not seem to be directly correlated with cytotoxicity, since cysteamine or higher concentrations of N‐OH‐pHAA inhibited lipid peroxidation without decreasing cellular damage.
Effects of Penicillins in Vitro on Mucociliary Activity of Rabbit Trachea
Authors: Toremalm Nils Gunnar , Josefsson Kenneth , Klementsson Klas , Lagergren Ingrid
Published: July 2010

Abstract: The effect of eight penicillins on the mucociliary activity of rabbit trachea was tested in vitro. Carbenicillin and ampicillin had a minor inhibitory effect. Penicillin G and V and pheneticillin were a little more ciliestatic. Propicillin, cloxacillin and dicloxacillin were most toxic. The mucociliary toxicity increased with increasing lipophilicity of the penicillins and correlated well with their known neurotoxic in vivo effects.
Interaction between Diphenolic Laxatives and Intestinal Bacteriain Vitro
Authors: Bergan Tom , Fotland Marit Hallaråker , Sund Reidar Bredo
Published: July 2010

Abstract:The ability of the laxative diphenols desacetylbisacodyl, oxyphenisatin, and phenolphthalein to inhibit growth and cause leakage of potassium ion from microbial cellsin vitrowas studied with 25 aerobic and 25 anaerobic bacterial strains. None of the aerobes, but some of the anaerobes showed growth inhibition. Potassium release assayed by flame photometry was observed in strains which showed growth inhibition, but also in other strains including anaerobes and aerobes. The highest antibacterial activity among the diphenols was observed with phenolphthalein and the least with desacetylbisacodyl; this relationship was noted for both growth inhibition and potassium release. Enzymatic hydrolysis of picosulphate to the free diphenol desacetylbisacodyl carried out by three strains of anaerobic bacteria was indicated by high pressure liquid chromatography.
Selective Affinity of Dimethyl Sulphoxide (DMSO) and 2‐amino‐4‐phenylsulphonylbenzenesulphonamide (NSD 3004) for the Large Intestinal Mucosa of Mice
Authors: Brandt I. , Brittebo E. B. , Larsson Y. , Lindqvist N.‐G. , Ullberg S.
Published: July 2010

Abstract: Whole‐body autoradiography of 14C‐labelled dimethyl sulphoxide and 35S‐labelled 2‐amino‐4‐phenylsulphonylbenzenesulphonamide revealed a selective accumulation of labelled substance in the large intestinal mucosa of mice. The mechanism of accumulation is discussed with regard to previous results on sulphone‐containing compounds with tissue‐specific distribution patterns.
Pharmacokinetics of Hydroflumethiazide during Repeated Administration in Congestive Heart Failure
Authors: Brørs O.
Published: July 2010

Abstract: The renal elimination and accumulation of hydroflumethiazide (HFT) during repeated oral administration was investigated in patients with congestive heart failure (CHF). When four doses of HFT were given with 24 hr intervals, the mean 24 hr urinary excretion of HFT was 55–65% of the dose after 75 mg and 53–57% after 150 mg. 24 hr excretion of HFT was not significantly higher after the fourth dose as compared with the first. The renal plasma clearance of HFT was significantly correlated with creatinine clearance (P<0 .01). The biological half‐life (t½β) of HFT ranged from 6.5–27.9 hrs. Mean t½β was shorter (P<0 .05) after 75 mg (9.2 hrs) than after 150 mg doses (14.1 hrs). The disposition rate constant of HFT was not significantly correlated with creatinine clearance or with renal plasma clearance of HFT, indicating that the volume of distribution was reduced at reduced renal function.
N‐Demethylation of Aminopyrine by the Nasal Mucosa in Mice and Rats
Authors: Brittebo Eva B.
Published: July 2010

Abstract:N‐demethylation of aminopyrine was demonstrated in the nasal mucosa of C57 B1 mice and Sprague‐Dawley rats by measurements of the14CO2formed at incubation of14C‐aminopyrine with tissue‐slices. The metabolism of aminopyrine by the nasal mucosa was induced by phenobarbital pretreatment and susceptible to inhibition with metyrapone and SKF 525 A suggesting the presence of a cytochrome P‐450‐dependent enzyme system in the tissue. Immediately after injection of14C‐aminopyrine in rats a uniform distribution of radioactivity in the body was recorded. After thirty minutes, however, a preferential localization of radioactivity was found in the nasal mucosa and in the liver. By pretreatment with metyrapone the uptake of radioactivity in the nasal mucosa and in the liver was blocked suggesting that the observed accumulation of radioactivity is due to metabolites.
Binding of Sulfinpyrazone and its Metabolites in Human Serum and in Solutions of Human Serum Albumin
Authors: Jakobsen P. , Pedersen A. Kirstein , Andreasen F.
Published: July 2010

Abstract:The binding of sulfinpyrazone, its sulfone metabolite and its sulfide metabolite to serum protein was studied by equilibrium dialysis. At 20 μg/ml 99.1% of the parent compound was bound in serum, whereas 99.8% of the sulfide and 98.3% of the sulfone were bound at this concentration. The binding of the three compounds were studied in diluted serum and in solutions of human serum albumin (HSA). There was no evidence of binding to proteins other than albumin. The association constants to primary and secondary binding sites and the number of binding sites were calculated. For the sulfide a lower K1‐value in serum (0.76·106M−1) than in the HSA solution (1.8·106M−1) indicated the possible presence of a competitively bound substance in serum. In undiluted serum no displacing effect of the sulfide on sulfinpyrazone binding was found when both compounds were present in a concentration of 20 μg/ml, but in a HSA solution a pronounced sulfide induced displacement of the sulfinpyrazone from its primary binding site was shown. Acetylation of HSA depressed the binding of sulfinpyrazone but in undiluted serum there was no other effect on sulfinpyrazone binding by the addition of acetylsalicylic acid than could be explained by the displacing effect of salicylic acid. At concentrations at 20 μg/ml of sulfinpyrazone and above 50 μg/ml of the displacing agent significant displacement was demonstrated with phenylbutazone, tolbutamide and salicylic acid.
Pharmacological Specificity of Conditioned Avoidance Response Inhibition in Rats: Inhibition by Neuroleptics and Correlation to Dopamine Receptor Blockade
Authors: Arnt Jørn
Published: July 2010

Abstract:The inhibitory effect of 36 neuroleptic compounds on conditioned avoidance response (CAR) and unconditioned escape response (UER) has been studied in rats. All neuroleptics antagonized CAR in doses below those inhibiting UER and below those inducing catalepsy. Stereospecificity was shown in two cases. Significant correlation was found between CAR inhibitory and cataleptogenic potency. Also inhibition of amphetamine induced stereotypy, affinity to3H‐haloperidol binding sitesin vitroand clinical potency was significantly correlated to CAR inhibition. CAR and UER inhibition induced by cis(Z)‐flupentixol and haloperidol was attenuated by scopolamine, but was only weakly influenced by methysergide and prazosin. Among a wide range of other CNS active compounds tested, CAR was inhibited by α1‐adrenergic antagonists, benzodiazepines, a barbiturate, GABA agonists, morphine and a serotonin agonist, but in doses inducing other motor disturbances. It is concluded that CAR inhibition is a sensitive test for dopamine receptor antagonists. However, additional α‐adrenergic activity found for some neuroleptics (e.g. clozapine, chlorprothixene) may contribute to the CAR inhibitory potency. Additional antimuscarinic activity of neuroleptics may moderately attenuate CAR inhibition whereas serotonin receptor blockade is of minor importance.
Comparison of the Effects of Different Arachidonic Acid Metabolites on Cyclic Nucleotide Accumulation in Human Peripheral Lymphocytes
Authors: Lanefelt Fred , Martinsson Arne , Hjemdahl Paul , Fredholm Bertil B.
Published: July 2010

Abstract: The effect of PGE1, PGE2, PGD2, PGF2α, PGI2, PGG2, PGA1, 12L‐HETE, arachidonic acid, 15‐HPETEa and linolenic acid on the accumulation of cyclic AMP in human peripheral lymphocytes was studied. PGE1, PGE2 and PGD2 were essentially equipotent as stimulators of cyclic AMP accumulation (threshold at about 10−8M and EC50 about 0.15 μM). PGF2α was about 20 times less potent, while PGG2, 12L‐HETE, 15‐HPETE, PGA1 and linolenic acid were inactive. PGI2 caused a weak stimulation between 5 and 600 nM and a secondary stimulation above 3 μM. Arachidonic acid had no effect on cyclic AMP levels up to 100 μM. PGE1, PGD2, PGI2 and PGF2α increased cyclic GMP in the concentrations that produced a rise in cyclic AMP, but the cyclic GMP increase was of smaller magnitude. Exogenous arachidonic acid was converted mainly to 12L‐HETE, HHT and thromboxane B2 by lymphocyte suspensions. This conversion could be accounted for by contamination with blood platelets. The results show that the degree of cyclic AMP accumulation in human lymphocytes following stimulation of arachidonic acid metabolism will be critically dependent upon which prostaglandins are in fact formed by cells surrounding the lymphocytes.
Uptake of Elemental Mercury and Activity of Catalase in Rat, Hamster, Guinea‐pig, Normal and Acatalasemic Mice
Authors: Eide Ingvar , Syversen Tore L. M.
Published: July 2010

Abstract:Uptake of elemental mercury after inhalation (3.5 mg/m3) and the activity of catalase in brain, liver, kidney and blood were investigated in rat, hamster, guinea‐pig, and normal and acatalasemic mice. The uptake of mercury in the species investigated varied considerably, being highest in the two strains of mice, followed by rat and hamster, and lowest in the guinea‐pig. The uptake seemed to be more dependent on pulmonary ventilation than on the activity of catalase. The two strains of mice were exposed to a wide range of mercury concentrations in air (0.002–3.5 mg/m3). The content of mercury in brain, liver and kidney was linearly dependent on the mercury concentration in the air, whereas in blood this relationship was exponential. At the lower concentrations of mercury in the inhaled air, the mercury level in blood was significantly lower, and in kidney higher in the acatalasemic mice compared to the normal ones. In acatalasemic mice the mercury content in liver was higher at all concentrations investigated, whereas in brain no difference between the two strains was found.
A Liquid Chromatographic Assay for 5‐Hydroxytryptophan, Serotonin and 5‐Hydroxyindoleacetic Acid in Human Body Fluids
Authors: Petruccelli Bruno , Bakris George , Miller Tom , Korpi Esa R. , Linnoila Markku
Published: July 2010

Abstract: We describe the precision and accuracy of a liquid chromatographic method, which uses internal standards, 6‐fluoroserotonin and 5‐hydroxyindolecarboxylic acid, in quantitating serotonin and 5‐hydroxyindoleacetic acid in human cerebrospinal fluid, plasma and urine. In addition, 5‐hydroxytryptophan is measured in the cerebrospinal fluid. The limit of sensitivity of this method is 0.1 pmol/injection, the peak height/concentration ratio is linear in the concentration range of 0.1 pmol to 50 μmol/injection, and the coefficient of variation is of the order of 15% at the limit of sensitivity and below 10% at amounts above 0.5 pmol/injection. No endogenous monoamines or their metabolites interfere with the quantitation of the substances of interest in the body fluids studied.
The Effect of pH Changes of Water on the Hepatic Metabolism of Xenobiotics in Fish
Authors: Laitinen Matti , Nieminen Mauri , Hietanen Eino
Published: July 2010

Abstract:In order to determine the effect of pH changes of water on the metabolism of xenobiotics, fish were exposed for 8 hours to the acidic water (pH 3). Two fish species were used, lavaret, (Coregonus lavaretus), and splake (Salvelinus fontinalis X Salvelinus namaycush). The metabolism of xenobiotics was monitored by analyzing aryl hydrocarbon hydroxylase, epoxide hydrase and ethoxycoumarin O‐deethylase activities as well as the activity of UDPglucuronosyltransferase using both p‐nitrophenol and 4‐methylumbelliferone as aglycones. A difference was found between species in measured basal activies. The aryl hydrocarbon hydroxylase activity, epoxide hydrase activity and ethoxycoumarin O‐deethylase activity were higher in the splake than in the lavaret, No clearcut differences were detected in UDPglucuronosyltransferase activities. When fish were exposed to water at pH 3, the aryl hydrocarbon hydroxylase acivity and epoxide hydrase activity in the splake were lower than in the control fish. The ethoxycoumarin O‐deethylase activity was higherin the lavarets at pH 3 than in the controls. The UDPglucuronosyltransferase activity was higher in both splakes and lavarets exposed to pH 3 when analyzed after trypsin digestion of microsomes and with 4‐methylumbelliferone as an aglycone.