bluuebunny/crossref_metadata_2025 huggingface dataset:
Stress‐protective Action of β‐Phenyl(GABA): Involvement of Central and Peripheral Type Benzodiazepine Binding Sites
Authors: Rägo Lembit , Kiivet Raul‐Allan , Adojaan Aleksander , Harro Jaanus , Allikmets Lembit
Published: March 2009

Forced swimming stress caused a significant increase in the density of central type benzodiazepine binding sites in rat cerebral cortex and hippocampus. The number of peripheral type benzodiazepine binding sites was also enhanced on blood platelets. The affinity of neither central nor peripheral type benzodiazepine binding sites was changed considerably after swimming stress. Pretreatment of rats with β‐(phenyl)GABA (100 mg/kg), a GABABagonist, almost completely eliminated the described changes of the both types of benzodiazepine binding sites caused by swimming stress. In an elevated plus‐maze model of anxiety β‐(phenyl)GABA itself was inactive but like diazepam effectively counteracted the behavioural effects of DMCM, a β‐carboline derivative with anxiogenic properties. The possible involvement of benzodiazepine receptors in the mechanism of action of β‐(phenyl)GABA is discussed.
Tissue Distribution, Metabolism, and Excretion of14C‐TCDD in a TCDD‐Susceptible and a TCDD‐Resistant Rat Straina
Authors: Pohjanvirta Raimo , Vartiainen Terrtu , Uusi‐Rauva Antti , Mönkkönen Jukka , Tuomisto Jouko
Published: March 2009

A comparative study was carried out in the most TCDD‐resistant [Han/Wistar (H/W), LD50 > 3000 μg/kg] and the most TCDD‐susceptible [Long‐Evans (L‐E), LD50 about 10 μg/kg] rat strain to assess the significance of kinetic factors in TCDD toxicity. Young adult males of both strains were administered 5 μg/kg (1.9 μCi/kg)14C‐TCDD intraperitoneally. Four rats per strain were killed at 4 hr, 1, 4, 8, 16, and 32 days after exposure. A total of 22 tissues along with blood and serum were sampled for liquid scintillation counting. From half of the animals, daily urine and faeces were also analyzed. In addition, 3 rats per strain were given 50 μg/kg (19 μCi/kg)14C‐TCDD and prepared for whole‐body autoradiography after 1, 4 or 8 days. The livers of two rats per strain killed at 4 hr, 4 or 16 days, and the excreta from two rats of both strains collected on days 1‐4, 5‐8, 13‐16, and 29‐32 after exposure were analyzed for metabolites of TCDD by high pressure liquid chromatography. The label was mainly excreted in faeces as metabolites of TCDD, and the half‐life of elimination was 20.8 (L‐E) or 21.9 (H/W) days. A very similar overall distribution pattern was observed in both strains irrespective of dose, and the liver was the major site of accumulation. Practically all liver14C‐activity was found as the parent compound. Moderate strain‐related differences were observed in the thyroid, thymus, prostate, adrenals, and brown and white fat, where lower values were recorded in H/W rats. Site‐dependent variation was detected in the brain. The results do not support the view that TCDD metabolism or disposition would have a major impact on the strain difference in TCDD lethality.
Verapamil‐Induced Inhibition of Theophylline Elimination in Healthy Humans
Authors: Nielsen‐Kudsk Jens Erik , Buhl Jørgen S. , Johanuessen Arne Cyron
Published: March 2009

The interaction between theophylline and verapamil was investigated in 7 healthy volunteers. Oral administration of verapamil in a dose of 120 mg t.i.d. for 7 days caused a significant inhibition of the elimination of theophylline (5 mg/kg intravenously). Theophylline clearance was reduced from 45.2 to 36.1 ml/hr/kg (20.1%; P<0.005). The apparent steady‐state volume of distribution of the drug was not influenced. The terminal half‐life of theophylline was increased from 6.80 to 8.23 hr (21.0%; P<0.001). Increased steady‐state plasma theophylline concentrations may thus be expected when verapamil is added to a drug regimen which includes theophylline.
Acute Inhibition of Human Renal Tubular Cell Growth by Cyclosporin A
Authors: Blæhr H. , Friis S.
Published: March 2009

Human proximal tubular cells were isolated and grown in culture for three passages. The proliferation of these cells were inhibited by the immunosuppressive drug cyclosporin A in dose dependent manner in the range of 250 to 2000 ng/ml growth medium. The cultures with low cell density were more sensitive to cyclosporin A compared to the cultures with high density, measured by the incorporation of 3H‐thymidine. The toxic effect of cyclosporin A on cells isolated from patients treated with cyclosporin A, did not differ from cells isolated from normal tissue. The calcium channel blocker, verapamil, reversed the inhibitory effect of low concentrations of cyclosporin A on cell proliferation. The electron microscopy showed that cells treated with cyclosporin A, had severe morphological alterations with rounded mitochondria and giant vesicles in the cytoplasma. The results support the hypothesis that the toxic effect of cyclosporin A may be mediated through an increased Ca++ influx into the proximal tubular cells.
Effects of Lithium and Rolipram Enantiomers on Locomotor Activity in Inbred Mice
Authors: Smith Donald F.
Published: March 2009

Rolipram is a racemic drug that increases brain cAMP availability by inhibiting phosphodiesterase. Lithium, on the other hand, reduces cAMP levels in brain by inhibiting adenylate cyclase and by increasing phosphodiesterase activity. Inbred strains of mice were used in the present study to determine whether the opposite effects of lithium and rolipram on cAMP levels were evident from behavioural effects of the drugs. In the first experiment, locomotor activity was measured in strains of male and female mice given an injection of either vehicle, (+)‐ or (‐)‐rolipram in order to find appropriate test conditions for studying interactions with lithium. (‐)‐Rolipram was more potent than its antipode in inducing hypokinesia, and the effects of (+)‐ and (‐)‐rolipram depended on mouse strain. In the second experiment, mice received lithium in their food for 3–4 weeks prior to testing, and they were then given an injection of vehicle, (+)‐ or (‐)‐rolipram before behaviour tests. Lithium reduced locomotor activity in mice given the vehicle, whereas it counteracted activity‐suppressant effects of rolipram. The behavioural findings are consistent with the opposite pharmacological effects of lithium and rolipram on cAMP, and support the notion that cAMP availability in brain may play a role in behavioural effects of lithium and rolipram.
Efect of NO2 on Lipids and Lipid Peroxidation in the CNS of the Guinea‐Pig
Authors: Farahani Hyder , Hasan* Mahdi
Published: March 2009

This study was undertaken to investigate the effect of nitrogen dioxide on some neurochemical parameters. Guinea‐pigs were exposed to NO2, 5 p.p.m. and 10 p.p.m. for 2 hr daily for five weeks. The results showed significant depletion of the total lipids and phospholipids content of the cerebral hemisphere, cerebellum, midbrain and spinal cord following nitrogen dioxide intoxication. The results further revealed significant diminution in the cholesterol content of the NO2 intoxicated animals in cerebral hemisphere, cerebellum and midbrain. But on the other hand the level was significantly enhanced in the spinal cord. Interestingly, the rate of lipid peroxidation was found enhanced in all the investigated brain areas, and with increasing dosage the effect was correspondingly pronounced.
Alloxan and Ninhydrin Inhibition of Hexokinase from Pancreatic Islets and Tumoural Insulin‐Secreting Cells
Authors: Lenzen Sigurd , Freytag Svenja , Panten Uwe , Flatt Peter R. , Bailey Clifford J.
Published: March 2009

Alloxan inhibited hexokinase activity in cytoplasmic fractions of transplantable radiation‐induced rat islet cell tumours, ob/ob mouse pancreatic islets, rat liver and rat kidney. Half maximal inhibitory concentrations of alloxan were greater than those previously found for half maximal inhibition of pancreatic islet or liver glucokinase. D‐glucose, preferentially the α‐anomer, and D‐mannose protected hexokinase activity against alloxan inhibition. 1,4‐Dithiothreitol completely protected against and partially reversed the alloxan inhibition of hexokinase. The ability of various dithiols to reverse the inhibition of hexokinase by alloxan was dependent on the spacing between the SH (thiol) groups. Only dithiols with intermediate spacing between the SH groups were effective. Dithiols with two vicinal SH groups such as 1,2‐dimercaptoethane and 2,3‐dimercaptopropanol (BAL) and dithiols with more widely spaced SH groups such as 1,5‐dimercaptopentane were ineffective. Thus a reaction of alloxan with two SH groups in the sugar binding site of the hexokinase with the formation of a disulfide bond may be involved in the reversible inhibition of the enzyme. Ninhydrin also inhibited hexokinase from all four tissues studied. The half maximal inhibitory concentrations of ninhydrin were lower than those of alloxan. Inhibition of hexokinase may be an important factor in the general cytotoxic action of ninhydrin. However, inhibition of pancreatic islet hexokinase is unlikely to be the initial event in the pancreatic B‐cell toxic action of alloxan, even if inhibition of hexokinase by high concentrations of alloxan may contribute to the B‐cell toxic action. Accordingly transplantable radiation‐induced rat islet cell tumours, in which glucose metabolism is primarily based on a high affinity glucose phosphorylating enzyme (hexokinase) activity, show resistance to alloxan toxicity. This contrasts with normal pancreatic B‐cells, which display high sensitivity to alloxan action and have a glucose metabolism critically dependent on the availability of low affinity glucose phosphorylating enzyme (glucokinase) activity.
Requirements for Drug Monitoring of Verapamil: Experience from an Unselected Group of Patients with Cardiovascular Disease
Authors: Husum Dorte , Johnsen Anders , Jensen Gorm
Published: March 2009

Serum verapamil and metabolite concentrations were determined by HPLC in 29 patients in routine treatment with verapamil, and 23 were in steady state. Dosage levels and corresponding mean trough levels (± S.D.) were as follows: 120 mg daily: 79.1 (±77) nmol/1, 240 mg daily: 173.3 (±200.1) nmol/1, 360 mg daily: 204 (±110.2) nmol/1 and 480 mg daily: 361.0 (±231.4) nmol/1. The variation coefficients were 97.3, 115.4, 54.0, and 62.1, respectively, thus showing considerable interpatient variation. Repeated determination of trough levels showed, in contrast, only small intrapatient variation (variation coefficient 35.8, 1.9, and 7.4, at the dosage levels 120, 240 and 340 mg per day). No significant correlation was found between serum verapamil levels age, sex, or weight. No significant effect of digoxin on the concentration of serum verapamil was found. No relation was observed between serum verapamil concentrations and desired effect or side‐effects. Two patients showed no measurable serum verapamil, but one of these had detectable levels of metabolites. Such patients may represent subgroups of fast metabolizers or non‐absorbers. Measurements of the metabolites nor‐verapamil, D 620 and D 617 indicated saturation of the first‐pass metabolism. In conclusion, therapeutic drug monitoring is not indicated during routine verapamil treatement, whereas single measurements of verapamil may be warranted in patients not responding to treatment in order to identify fast metabolizers or non‐absorbers.
Further Studies on the High‐Affinity Binding of3H‐Alaproclate to Membranes from Rat Liver and Some Other Tissues
Authors: Ross Svante B.
Published: March 2009

The high affinity binding of3H‐alaproclate to membranes in liver homogenates from naive rats and those treated with phenobarbital sodium, 75 mg/kg intraperitoneally, alaproclate hydrochloride, 40 mg/kg intraperitoneally proadifen hydrochloride, 40 mg/kg intraperitoneally once daily for 7 days and killed 24 hr after the last injection was examined. The treatment increased the normal number of alaproclate binding sites (Bmax: 1.1 nmol/g tissue, KD: 0.6 nM) by factors of about 10, 4 and 6, respectively. About 80% of the binding was localized to the microsomal fraction in both normal and phenobarbital treated rats. Ninety % of the alaproclate displaceable binding in a microsomal preparation of the normal liver was inhibited by low (nM) concentrations of proadifen whereas only about 20% in the liver preparations from phenobarbital treated rats was inhibited by low concentrations of proadifen. Thus, the main part of the induced binding sites was insensitive to proadifen. The same was found for the alaproclate and proadifen‐induced alaproclate binding sites. The stereoselectivity of alaproclate enantiomers for binding to the normal and the induced binding sites was different: the S–(–) form was 100 times more potent than the R–(+)‐ enantiomer in inhibiting binding of racemic alaproclate to the normal sites, whereas the latter form was 3 times more potent than the former in inhibiting the binding to the phenobarbital‐induced proadifen insensitive binding sites. High affinity for the alaproclate binding sites in normal liver seems to require an ester function since the keto analogues 2‐amino‐6‐(4‐chlorophenyl)‐5,5‐dimethyl‐3‐hexanone and especially 5‐amino‐1‐(4‐chlorophenyl)‐2,2‐dimethyl‐3‐hexanone were much less active than alaproclate, the isopropyl analogue 2‐(4‐clorophenyl)‐1,1‐dimethyl 2‐amino‐3‐methylbutanoate and proadifen. All other compounds tested had quite low affinity for the alaproclate binding sites in the liver. Quinidine was the most potent of these compounds in normal liver and desipramine in livers from phenobarbital treated rats. High or moderate high affinity alaproclate binding sites were also found in the lung, kidney, adrenal and heart.
Effects of Ethanol on Expiratory Neuronal Activities in Decerebrated Cats
Authors: Takeda Ryuji , Haji Akira
Published: March 2009

The effects of ethanol on two types of bulbar expiratory neurones, post‐inspiratory (early expiratory) and expiratory (late expiratory) neurones, were studied in decerebrated, paralyzed and artificially ventilated cats. Intravenous injection of ethanol (300 mg/kg) depressed the efferent activity in the phrenic and recurrent laryngeal nerves which displayed the augmenting discharge during inspiration and the decrementing discharge during the early stage of expiration (stage I expiration). It reduced the duration of expiration, with a preferential effect on stage I expiration. Out of 22 medullary respiratory neurones consisting of 14 post‐inspiratory and 8 expiratory neurones, 12 neurones were depolarized by ethanol and 10 neurones were hyperpolarized. In both cases, the respiratory fluctuations of membrane potential diminished and synaptic noises decreased. Input resistances of these neurones remained unchanged. Ethanol depressed the spike activity during stage I expiration of the post‐inspiratory neurones. In expiratory neurones, a suppression of firing was greater in stage I expiration than in later stages of expiration. The present results demonstrate that ethanol reduces the expiratory period mainly through the depression of the post‐inspiratory neuronal activity in the bulbar respiratory control mechanism.
An Analysis of the β2‐Adrenoceptor Selectivity in Three Series of β‐Adrenoceptor Agonists
Authors: Johansson Lars‐Håkan , Eliasson Eva Linder , Persson Henry , Rosengren Evald
Published: March 2009

The aim of the study was to analyse the β2‐adrenoceptor selectivity earlier found in two series of catecholamines and one series of resorcinolamines (Johanssonet al.1986). The affinity of the compounds was assessed in binding studies in preparations from the guinea‐pig left heart ventricle (β1‐adrenoceptors) and the soleus muscle (β2‐adrenoceptors) using3H‐CGP‐12177 as radioligand. Further, the activation of the adenylate cyclase by the compounds was studied in the same preparations. Selectivity quotients were obtained from both functional effects and from affinity and adenylate cyclase activating studies. There was a good correlation between the selectivity quotients obtained in these two ways. Tertiary butyl substitution on the amino nitrogen gave the highest β2‐adrenoceptor selectivity in both the catechol and resorcinol series. In comparison with their isopropyl substituted analogues the β2‐adrenoceptor selectivity of these compounds (KWD 2026 and terbutaline) was mainly due to a change in affinity for the β1‐ and β2‐adrenoceptors and, to a lesser degree, a change in intrinsic efficacy.
Prolonged Action Potential Duration of Guinea‐Pig Heart Muscle after Pethidine
Authors: Helgesen Knut G. , Refsum Helge
Published: March 2009

Since recent experiments indicated class III antiarrhythmic properties of pethidinein vitro, we studied cardiac effects of pethidinein vivo.Monophasic action potentials at different pacing rates were recorded from the left ventricular epicardium of pentobarbital anaesthetized guinea‐pigs by means of suction electrode catheter. Intravenous injection of pethidine 2 mg/kg prolonged the action potential duration, and increased left ventricular developed pressure and dP/dt max, compared to animals receiving saline only. It is concluded that pethidine appears to have class III antiarrhythmic properties.
Glucuronidation of Codeine and Morphine in Human Liver and Kidney Microsomes: Effect of Inhibitors
Authors: Yue Qunying , von Bahr Christer , Odar‐Cederlöf Ingegerd , Säwe Juliette
Published: March 2009

Glucuronidation of codeine was detected and compared with that of morphine in microsomes from human livers and kidneys. Vmaxvalues for codeine‐6‐glucuronide (C6G) were 0.54±0.24 and 0.74±0.35 nmol/mg/min. in the livers and 0.10 and 0.13 nmol/mg/min. in the kidney, respectively, when codeine and UDP‐glucuronic acid (UDPGA) were incubated with microsomal preparation. The corresponding Kmvalues were 2.21±0.68 and 1.41±0.36 mM in the livers and 6.69 and 4.12 mM in the kidney. The average codeine glucuronyltransferase (GT) activity was 14‐fold lower in the six kidneys than in the 11 livers. Higher GT activities were observed in liver microsomes from patients who had been exposed to enzyme inducers. Rates of glucuronide formation from morphine correlated significantly with those from codeine in both human liver and kidney microsomes. Morphine, amitriptyline, diazepam, probenecid and chloramphenicol inhibited codeine glucuronidation with Kivalues of 3.6, 0.13, 0.18, 1.7 and 0.27 mM, respectively.
Deuterium D(V/K) Isotope Effects on Ethanol Oxidation in Hepatocytes: Importance of the Reverse ADH‐Reaction
Authors: Lundquist Frank , Iversen Henning L. , Hansen Lillian L.
Published: March 2009

The kinetic deuterium isotope effect, D(V/K), on ethanol oxidation was measured on hepatocytes from rat and pig by the radiometric competitive method using 14C‐labelled ethanol containing deuterium in the (1‐R)‐position. The corrected D(V/K) values of 2.68 and 2.80 for rat and pig hepatocytes respectively were significantly different, suggesting differences in the amount of non‐ADH ethanol oxidizing activity. The apparent isotope effects declined rapidly with time when acetaldehyde was present in the medium as a result of the reduction to ethanol of the [14C]‐acetaldehyde formed from the double labelled ethanol by alcohol dehydrogenase (ADH). Fructose and cyanamide caused the acetaldehyde concentration during ethanol oxidation to increase by entirely different mechanisms, and the isotope effect to decrease with time, as did also the addition of acetaldehyde. The apparent first order rate constant for the reverse ADH reaction, assuming the reactants to be acetaldehyde and the ADH‐NADH complex, was determined by two methods giving comparable results. In the presence of semicarbazide, which removes acetaldehyde, the isotope effect was nearly constant. This was the case also when the acetaldehyde concentration was very low (< 1 μM) for other reasons, as in hepatocytes from starved animals. A mathematical formula describing the expected decrease of the apparent isotope effect with time was derived. The different response of pig and rat hepatocytes to addition of fructose (the ‘fructose effect’) is suggested to be caused by differences in activity of aldehyde dehydrogenases in the two species.
Vitamin E and Glutathione are Required for Preservation of Microsomal Glutathione S‐Transferase from Oxidative Stress in Microsomes
Authors: Tampo Yoshiko , Yonaha Masanori
Published: March 2009

Glutathione (GSH) inhibited lipid peroxidation induced by NADPH‐BrCCl3 in vitamin E sufficient microsomes, but did not in phenobarbital (PB)‐treated microsomes (containing about 60% of normal vitamin E) or in vitamin E‐deficient microsomes (containing about 30% of normal vitamin E). There was a good correlation between the increased formation of CHCl3 from BrCCl3 in the presence of GSH under anaerobic conditions and the vitamin E level in the microsomes. A normal level of vitamin E in microsomes was thus very important for GSH‐dependent inhibition of lipid peroxidation and for the efficient formation of CHCl3 from BrCCl3. Bromosulfophthalein (BSP) eliminated the effects of GSH on lipid peroxidation and CHCl3 formation. The apparent Km and Vmax of substrates for GSH S‐transferase were changed by in vivo depletion of vitamin E in microsomes, and the Vmax/Km values were significantly reduced. The enzyme activity in microsomes was inactivated following the loss of vitamin E during in vitro lipid peroxidation, and GSH prevented the loss of vitamin E and protected the enzyme from attack by free radicals. GSH inhibited lipid peroxidation induced by NADPH‐Fe2+ and the loss of GSH S‐transferase activity during the peroxidation in PB‐treated microsomes, but did not in the case of induction by NADPH‐BrCCl3. A possible relation between the microsomal GSH S‐transferase activity and defense by GSH against lipid peroxidation in microsomes is discussed.
Studies of the Effect of Glyceryl Trinitrate and Cyclic GMP on Calcium Turnover in Bovine Mesenteric Artery
Authors: Ahlner Johan , Axelsson Krister L. , Karczewski Peter , Andersson Rolf G. G.
Published: March 2009

It was recently observed that the relaxation induced by glyceryl trinitrate (GTN) showed a biphasic concentration‐response curve; a high‐sensitivity component represented by concentrations < 1 nM and a low‐sensitivity component represented by concentrations > 1 nM. The effect of two glyceryl trinitrate concentrations (0.1 nM and 1 μM) were tested on the uptake of45Ca2+to tissue pieces of bovine mesenteric arteries (BMA) as well as on the uptake of45Ca2+to a microsomal preparation of BMA. The effect of GTN and 8‐Br‐cGMP was also studied on the IP3‐induced release of Ca2+from the microsomal preparation preloaded with45Ca2+. The influence of IP3and GTN on the activity of Ca2+‐ATPase in the microsomal preparation was tested as well. The phenylephrine‐stimulated uptake of Ca2+to tissue pieces of BMA was significantly reduced by the high GTN‐concentration (1 μM) but not by the lower concentration. The uptake of Ca2+to the microsomal preparation was significantly stimulated by the two GTN‐concentrations tested, as well as by 8‐Br‐cGMP (0.1 mM). The calcium release induced by IP3(1 μM) from the microsomal preparation was inhibited by both the low and the high GTN‐concentration and by 8‐Br‐cGMP (0.1 mM). The Ca2+‐ATPase activity was stimulated by both GTN‐concentrations tested while it was inhibited by IP3. It is concluded that GTN is able to induce a reduction of the free intracellular Ca2+by several mechanisms, which are of importance for the relaxation represented by the high‐affinity component. The low‐affinity component in addition reduces the inflow of Ca2+over the plasma membrane.
Effects of α2‐Adrenergic Drugs on the Alcohol Consumption of Alcohol‐Preferring Rats
Authors: Korpi E. R.
Published: March 2009

The effects of seven‐day subcutaneous infusion of an α2‐adrenoceptor agonist, medetomidine, and an α2‐adrenoceptor antagonist, atipamezole, on the voluntary alcohol consumption of alcohol‐preferring rats were studied. The drugs were administered by means of implanted osmotic minipumps. Sham‐operated control rats had no pumps implanted. The rats had a free choice between 10% alcohol and plain water for 30 days before pump implantation and again for six days starting 24 hr after the operation. Atipamezole increased the alcohol consumption during the first day of free choice. Medetomidine had no significant effect. During the remaining period of infusion, the alcohol consumption did not differ from that preceding the pump implantation in each treatment group. Animals in the atipamezole group gained more weight during the seven‐day trial than did those in the medetomidine and control groups. The amine changes in different regions of the brain were consistent with medetomidine decreasing and atipamezole increasing the noradrenaline turnover. The present results indicate that specific drugs acting on the α2‐adrenoceptors produce only minor changes in the voluntary alcohol drinking of alcohol‐preferring rats.
The Isolated Mouse Atria as a New Model for Testing Cardioactive Drugs with Special Reference to Doxorubicin (Adriamycin®)
Authors: Hermansen K. , Rasmussen I. M. N. , Schou H. S.
Published: March 2009

Spontaneously beating isolated atria from mice were used as a new in vitro model to characterize the mechanism of the cardiotoxic action of the anthracycline cytostatic doxorubicin (Adriamycin®). After stabilization at 28° the atria showed a contractile rate and – force of 284±31 (S.D.) beats/min. and 49±6.5 mg. Doxorubicin (Dox) (10‐6‐10‐5 M) had a positive chronotropic action per se and decreased the pD2 for the chronotropic action of isoprenaline in a dose‐dependent way. However only the effect of the higher concentration proved statistically significant, a concentration which also caused a marked decrease (63%) of the Emax. Pretreatment with Dox 15 mg/kg intraperitoneally 72 hr previously did not influence the pD2 but caused a significant increase in the Emax of the isoprenaline concentration response curve. The results indicate that Dox in vitro interferes with the β‐adrenoceptor function of isolated mouse atria in an unspecific way and that the subacute cardiotoxicity of Dox in mice is probably not due to interference with the β‐adrenoceptor system. Further it is concluded that isolated atria from mice may be a useful model for testing cardioactive drugs.
Electromechanical Effects of Two Low Osmolality Contrast Media, Ioxaglate and Iohexol, on Isolated Rat Atria
Authors: Tande Pål M. , Klew Nils‐Einar , Refsum Helge
Published: March 2009

This study aimed at investigating the direct effects of two low osmolality radiographic contrast media, iohexol (non‐ionic) and ioxaglate (ionic), on transmembrane action potentials, contractile force and refractoriness of isolated rat atrial preparations. Superfused with 10% solution, ioxaglate induced a biphasic mechanical response, initially decreasing and thereafter increasing contractile force. The same concentration of iohexol only increased contractile force. The two contrast media increased the resting membrane potential, action potential amplitude and rate of depolarization to the same extent. Iohexol prolonged repolarization. Both contrast media decreased the effective refractory period. The direct effects of contrast media on myocardial contractility in this study can explain the different haemodynamic effects of iohexol and ioxaglate in vivo. The observed effects on the action potentials in vitro can explain commonly observed ECG changes during coronary arteriography. The changes in depolarization, repolarization and refractoriness are probably related to the arrhythmogenic properties of these contrast media.
Cardiovascular and Ventilatory Effects of Various Acidic, Basic and Neutral L‐Amino Acids in Normotensive Rats
Authors: Ekholm Sari , Karppanen Heikki
Published: March 2009

Cardiovascular effects have been attributed to the amino acids which are precursors of catecholamines or other neurotransmitters. To study if even other amino acids may exert cardiovascular or ventilatory effects, a number of various acidic, basic and neutral L‐amino acids were injected intravenously to anaesthetised normotensive rats at the doses of 0.2‐1.6 mmol/kg. All amino acids were able to produce either blood pressure, heart rate or ventilation rate changes. Hence, in this study the production of cardiovascular or ventilatory effects was not limited to the known precursors of neurotransmitters. Therefore, in addition to increased formation and release of neurotransmitters, other mechanisms are apparently involved in the cardiovascular and ventilatory effects of various L‐amino acids.
Myocardial Effects of Adrenaline, Isoprenaline and Dobutamine at Hypothermic Conditions
Authors: Riishede Lars , Nielsen‐Kudsk Folmer
Published: March 2009

The pharmacodynamic myocardial effects of adrenaline, isoprenaline and dobutamine were studied in isolated, perfused and spontaneously beating rabbit hearts at hypothermic conditions. Cardiac contraction amplitude increased from the control value at 37° set equal to 100% to about 165% at 22°, whereas contraction velocity decreased to 52%, frequency to 30% and oxygen consumption to about 19%. At 22° all drugs produced pronounced positive inotropic and chronotropic effects. Em‐values related to contraction velocity, frequency and oxygen consumption were for isoprenaline 152, 98 and 136%, respectively, for adrenaline 127, 100 and 198% and for dobutamine 120, 86 and 165%, respectively. The corresponding EC50‐values decreased and a marked left‐shift of the log‐concentration response curves was observed as an expression of increased myocardial sensitivity to the drugs. Em for contraction velocity for dobutamine was distinctly reduced at 32 and 27° and for adrenaline at 27° in comparison to the increase seen at 22 and 37°. Em for oxygen consumption showed for all drugs an increase at decreasing temperatures. The frequency‐corrected QTc‐interval decreased slightly to moderately during exposure to the drugs at hypothermic conditions. None of the drugs caused arrhytmias during the experiments. Coronary flow rate decreased only moderately at the higher drug concentrations at decreased temperatures. Dobutamine and adrenaline at 37° and isoprenaline at 37 and 22° caused an increase of Em for oxygen consumption that was slightly less than proportional to the increase of Em for contraction velocity.
Structure and Pulmonary Toxicity Relationship on O,O‐Dimethyl S‐Alkyl Phosphorothioate Esters
Authors: Hasegawa Jun‐ichi , Wada Yasuhiko , Sageshima Masato , Suzuki Masahiro , Kamiyama Sigetosi , Abe Nobuo , Koizumi Akio
Published: March 2009

The structure‐pulmonary toxicity relationship was investigated using three different O,O,S‐trimethylphosphorothioate (OOS‐TMP) analogues, which is known to induce a typical mortality pattern (dealyed death) and pulmonary injury; O,O‐dimethyl S‐ethyl (OOS‐DMEP), O,O‐dimethyl S‐propyl (OOS‐DMPP), and O,O‐dimethyl S‐butyl (OOS‐DMBP) phosphorothioates. The mortality pattern in rats dosed with OOS‐DMEP was similar to the “delayed death” pattern: the LD50s in rats for OOS‐DMEP decreased dramatically from more than 200 mg/kg within 24 hr to 41.1 (males) or 13.8 (females) mg/kg 7 days after treatment while the LD50s in rats for OOS‐DMPP and OOS‐DMBP did not. Histopathological examinations revealed that OOS‐DMEP induced pulmonary oedema and bleeding at a dose of 1/2 LD50 by 72 hr after dosing while the other two compounds did not. Thus, it was concluded that OOS‐DMEP induces pulmonary injury, thereby eliciting the “delayed death” mortality pattern.
Pharmacokinetics of Terodiline and a Major Metabolite in Dogs with a Correlation to a Pharmacodynamic Effect
Authors: Hallén B. , Grälls M. , Brötell H. , Strömberg S.
Published: March 2009

The pharmacokinetics and pharmacodynamics of the anticholinergic and calcium antagonistic drug terodiline, N‐tert‐butyl‐1‐methyl‐3,3‐diphenylpropylamine, have been studied in beagle dogs. The bioavailability was about 25% (0.15 and 0.5 mg/kg), the terminal half‐life 3 hr, the systemic clearance 40 ml/min. kg, the volume of distribution (Vβ) about 7 1/kg and the unbound fraction in serum 0.14. p‐Hydroxyterodiline and p‐hydroxy‐m‐methoxyterodiline were quantitated and constituted 15–40% and 25%, respectively, of the amount excreted in urine (about 60% of the dose) and were the main metabolites, as in man. The dog was used as an experimental model to study the chronotropic effect. An increased heart rate was observed after acute administration of high doses of terodiline as well as after p‐hydroxyterodiline. A 20% increase in heart rate was observed at a mean serum concentration of 1086 and 1010 μg/1 following intravenous injection of terodiline or p‐hydroxyterodiline, respectively. The corresponding unbound concentrations were 150 and 474 μg/1. The potency ratios of terodiline/p‐hydroxyterodiline was 0.9±0.2 (based on total concentrations) and 3.2±0.8 (based on unbound concentrations). The estimated potency of parent drug and main metabolite and the fact that p‐hydroxyterodiline constitutes 10–20% of the terodiline steady‐state level in man, indicate that the contribution of the metabolite to the chronotropic effect observed in clinical studies is minor.
Studies on the Role of Lipid Peroxidation in the Acute Toxicity of TCDD in Rats*
Authors: Pohjanvirta Raimo , Sankari Satu , Kulju Tauno , Naukkarinen Anita , Ylinen Markku , Tuomisto Jouko
Published: March 2009

Lipid peroxidation has been shown to be enhanced following exposure to 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD), but its role in TCDD toxicity is unclear. The present study was undertaken to further elucidate the relations between lipid peroxidation and TCDD lethality. A time course and dose‐response experiment in Long‐Evans (L‐E; LD50 ca. 10 μg/kg) and Han/Wistar (H/W; LD50 > 3000 μg/kg) rats showed that hepatic lipid peroxidation, measured as the amount of thiobarbituric acid‐reactive substances (TBA‐RS), was induced by TCDD dose‐dependently in L‐E, but not in H/W rats. Hepatic glutathione peroxidase activity was suppressed in much the same manner in both strains. Lipid peroxidation correlated with body weight loss in L‐E rats alone. When 500 μg/kg of TCDD was given to L‐E rats, lipid peroxidation increased about 3‐fold on Day 11 in the liver, while no change was seen in cardiac or renal TBA‐RS. The pair‐fed controls did not survive the 11‐day test period and exhibited gastrointestinal hemorrhages. At 6 days, liver atrophy and elevated (over 2‐fold) TBA‐RS values were recorded in pair‐fed controls but not in their TCDD‐treated counterparts. TCDD decreased hepatic glutathione peroxidase activity by almost 50% at 6 days, while pair‐feeding was without effect. Liver morphology was different between TCDD‐treated and pair‐fed rats. Moreover, the livers of TCDD‐treated L‐E rats contained much higher concentrations of probably peripheral fat‐derived fatty acids than did the livers of pair‐fed orad libitumcontrol rats. Restricted feeding over 6 days induced hepatic lipid peroxidation more in H/W than in L‐E rats. Endotoxin increased liver TBA levels similarly in both strains having an additive effect with high doses of TCDD in H/W rats. Added as a 0.5% concentration in chow, butylated hydroxyanisole (BHA), but not ethoxyquin, tended to increase survival rate and time in L‐E rats exposed to 20 μg/kg of TCDD; at 50 μg/kg the only survivor was again in the BHA group. However, neither antioxidant had any effect on initial body weight loss. It is concluded that lipid peroxidation mainly arises as a secondary phenomenon in TCDD toxicity, is not the cause of the typical histopathological liver lesion, but may contribute to lethality.
Fat Content and Xenobiotic Concentrations in Human Milk: Validation of an Enzymatic Assay of Milk Fat
Authors: Matheson I. , Foss O. P. , Skaare J. U.
Published: March 2009

This study reports the validation of an automatic assay for milk triglycerides, as well as the association between milk xenobiotic concentrations and milk triglycerides. The correlation between this assay and a gravimetric reference method for total fat was good (r = 0.997). Triglycerides and xenobiotics were measured in breast milk sampled from one mother. She received two water‐soluble drugs, tetracycline and doxycycline in two courses. The levels of organochlorines (DDE, PCB) were also measured and related to those of fat in milk samples from this mother. These and previous results indicate that milk triglyceride variations influence the concentrations of lipophilic xenobiotics in milk.
Acute Behavioural Effects of the Organophosphates Sarin and Soman in Rats
Authors: Nieminen Sakari A. , Lecklin Anne , Heikkinen Outi , Ylitalo Pauli
Published: March 2009

The effects on behaviour of single subtoxic doses of two potent organophosphorous compounds, sarin (isopropyl methylphosphonofluoridate, 12.5 and 50 μg/kg, intraperitoneally) and soman (pinacolyl methylphosphonofluoridate, 4 and 20 μg/kg, intraperitoneally) were studied in male Wistar rats. In the open field test, soman dose‐dependently decreased rearing and ambulation and increased non‐mobile exploration. The higher dose of sarin changed only the rearing and grooming behaviour. Sarin and soman decreased locomotor activity on the Animex for at least one hour at the beginning of the monitoring period. In the doses used, both organophosphates inhibitied acetylcholinesterase (AChE) activity significantly in the blood. The results suggest that small doses of sarin and soman have inactivating effects on the behaviour of rats. Although the findings cannot be extrapolated directly to behavioural changes in man, they indicate that subtle behavioural dysfunctions could also occur in humans at exposures which do not cause acute toxicity.
Demethylation Pathways in Caffeine Metabolism as Indicators of Variability in 1,1,1‐Trichloroethane Oxidation in Man
Authors: Berode Michele , Boillat M.‐A. , Guillemin M. P. , Wu Mei‐Miau , Savolainen H.
Published: March 2009

Twenty volunteers were exposed to 191 ± 7 p.p.m. 1,1,1‐trichloroethane or 50 ± 2 p.p.m. perchloroethylene vapour for 6 hr. They were then evaluated for their rate of caffeine metabolism, mephenytoin hydroxylation and debrisoquine hydroxylation. Seven subjects were idendified as ‘fast acetylators’ of caffeine and one person as a slow metabolizer of debrisoquine. The “slow acetylators” exposed to perchloroethylene excreted an average of 3.83 ± 0.35 mg trichloroacetic acid within 24 hr (N = 13, ± S.E.) and the ‘fast acetylators’ 3.58 ± 0.48 mg (N = 7, ± S.E.). The excretion of trichloroethanol by the same persons after 1,1,1‐trichloroethane exposure was 14.1 ± 1.12 mg and 16.7 ± 1.48 mg, respectively. The excretion of trichloroacetic acid in the latter exposure varied significantly between the seven ‘fast’ and 13 ‘slow acetylators’ (0.43 ± 0.08 mg versus 1.03 ± 0.19 mg; ± S.E.; P = 0.037). A multiple linear regression analysis confirmed this association when other factors, such as body weight, creatinine clearance, smoking habit and alcohol consumption, were taken into account. One volunteer proved to be a poor hydroxylator of debrisoquine and excreted half the amount of trichloroacetic acid in the perchloroethylene exposure and half the amount of trichloroethanol in the 1,1,1‐trichloroethane exposure compared to the others. A reduction in the solvent metabolism could thus be predicted by the debrisoquine test. On the other hand, the caffeine test predicted faster oxidation of trichloroethanol which could be of toxicological and pharmacological importance e.g. in the clinical use of chloral.
The Effects of Alcoholsin Vitroon the Nervous Cell Membrane Measured by Changes in the (Ca2+/Mg2+) ATPase Activity and Fluidity of the Synaptosomal Membrane
Authors: Edelfors Sven , Ravn‐Jonsen Andree
Published: March 2009

The effect of various alkanols on the central nervous system was studied by using rat brain synaptosomal membranes as anin vitromodel. The activity of (Ca2+/Mg2+)ATPase and the membrane fluidity were determined. The n‐alkanols exhibited an increased molar inhibition of the ATPase activity with an increase in the carbon chain length up to 1‐octanol. 1‐octanol and 1‐decanol caused a biphasic effect on the ATPase activity depending on the alkanol concentration, whereas 1‐dodecanol caused a stimulation of the ATPase activity. All alkanols studied caused an increased fluidity of the membrane. Our results indicate that the effect of alkanols on the ATPase activity depends on changes in the border layer between the membrane and the surrounding medium and on a binding of the alkanols to the enzyme molecule. Furthermore, the two‐way effect of 1‐octanol and 1‐decanol and the stimulatory effect of 1‐dodecanol indicate that more mechanisms are involved. In addition, the results indicate that changes in the membrane fluidity do not seem to be a prerequisite of the ATPase inhibition.
Effect of Oral Activated Charcoal on the Pharmacokinetics of Quinidine and Quinine Administered Intravenously to Rabbits
Authors: Hasan Mazen M. , Hassan Mohammad A. , Rawashdeh Nayel M.
Published: March 2009

The pharmacokinetics of quinidine and quinine following intravenous administration (10 mg/kg) with and without concurrent treatment with oral activated charcoal was studied in the rabbit. Marked differences were observed in the pharmacokinetic parameters. Compared to quinidine, quinine was characterized by larger volume of distribution (Vd), systemic clearance (CI) and elimination rate constant (Kel), and smaller half‐life of elimination (t1/2), mean residence time (MRT) and area under the curve (AUC). Activated charcoal administered orally (15 g) significantly decreased the serum concentrations of quinidine but not quinine. Furthermore, charcoal treatment significantly enhanced the systemic elimination of quinidine as indicated by the significant increase in CI and decrease in t1/2, MRT and AUC. By contrast, activated charcoal had no significant effect on the pharmacokinetic parameters of quinine. Differences between quinidine and quinine in respect to the effect of activated charcoal on the systemic elimination of these drugs seem at least, in part, dependent on dispositional factors. The high CI and Vd of quinine in the rabbit are probably factors that mask the effect of charcoal on the elimination of this drug.
Acute and Carry‐Over Effects of Brotizolam Compared to Nitrazepam and Placebo in Monotonous Simulated Driving
Authors: Törnros Jan , Laurell Hans
Published: March 2009

Eighteen healthy volunteers of both sexes, aged 20–35 years, were tested in the morning after three nights of medication with brotizolam 0.25 mg, nitrazepam 5 mg or placebo on a monotonous simulated driving task. The effect measures were subsidiary auditory reaction time and time outside road. Measurements of self‐rated alertness were carried out as well. No effects were demonstrated from treatments on either measure. Nitrazepam however tended to score worst on all measures, except time outside road which could not be analysed with respect to statistical significance because of an insufficient number of subjects leaving the road. Twelve of the subjects were also tested immediately after drug intake on the first night of each medication period. Reaction time decrement was observed in both active drugs conditions with no difference between the two. The other measures, however non‐significant, pointed in the same direction with the greatest decrement for nitrazepam.
Sympathoexcitatory Action of a Novel Muscarinic Receptor Agonist, AF102B, and its Blockade by Pirenzepine
Authors: Yoshioka Mitsuhiro , Togashi Hiroko , Matsumoto Machiko , Morii Ken , Saito Hideya
Published: March 2009

The pharmacological effects of a novel, selective muscarinic (M1) receptor agonist, AF102B (cis‐2‐methyl‐spiro‐(1,3‐oxathiolane‐5,3′)‐quinuclidine hydrochloride hemihydrate), on sympathetic nerve activity are described. Intravenous administration of AF102B (1 and 10 mg/kg) produced a dose‐dependent increase in cardiac sympathetic nerve activity accompanied by tachycardia in spinal‐intact rats. In addition, AF102B (10 mg/kg) caused a marked increase in cardiac sympathetic nerve activity and heart rate in pithed rats. Pirenzepine (50 μg/kg) inhibited these sympathoexcitatory effects of AF102B (10 mg/kg) in pithed rats. These findings suggest that AF102B possesses a sympathoexcitatory action which is mediated by M1‐receptors.
Effects of Age and Antiepileptic Drugs on Plasma Levels and Kinetics of Clobazam and N‐Desmethylclobazam
Authors: Bun Hot , Monjanel‐Mouterde Suzanne , Noel Françoise , Durand Alain , Cano Jean‐Paul
Published: March 2009

The authors monitored the plasma levels of clobazam (CLO) and its principal metabolite, N‐desmethylclobazam (NCLO) during chronic treatment of more than 400 epileptic patients receiving different co‐medications, such as phenytoin (PH), carbamazepine (CBZ), sodium valproate (VPA) and phenobarbital (PB). This study investigated the influence of age and antiepileptic drugs on plasma levels of CLO and NCLO. Plasma concentrations measured 3 hr after morning administration of CLO varied from 30 to 700 ng/ml/mg/kg/d for CLO, and from 160 to 7000 ng/ml/mg/kg/d for NCLO. Plasma levels of CLO were higher in patients aged 20–30 years. NCLO concentrations increased with age up to 20 years. Coadministered antiepileptic compounds significantly decreased maximal plasma levels of CLO. Moreover, PH and CBZ a significantly increased the plasma levels of NCLO. Results on the influence of CBZ on CLO kinetics were confirmed in a group of ten patients receiving PB and VPA and later PB, VPA and CBZ as CLO associated drugs. The influence of VPA on the pharmacokinetics parameters of CLO was also evaluated in a patient in the latter group.
The Effects of Vadocaine, Dextromethorphan, Diphenhydramine and Hydroxyzine on the Ciliary Beat Frequency in Rats in Vitro
Authors: Karttunen Pekka , Silvasti Matti , Virta Pasi , Saano Veijo , Nuutinen Juhani
Published: March 2009

Mucociliary function is a major cleansing mechanism of the respiratory tract. Many drugs used in the treatment of respiratory diseases impair the ciliary beat frequency (CBF) of mucous membrane. Our aim was to study by means of a photoelectric technique, the effects of two antitussives ‐ dextromethorphan and vadocaine ‐ and two antihistamines ‐hydroxyzine and diphenhydramine ‐ on the rat tracheal CBF in vitro. The CBF was measured from tracheal explants immersed in drug solutions. Dextromethorphan (1.0 mg/ml and 10.0 mg/ml) caused 16.9–20.8% decrease in the CBF during the 40 min. measurement period. Vadocaine (0.1 mg/ml and 0.5 mg/ml) decreased the CBF by 6.9%. Higher vadocaine concentrations caused a dose‐dependent inhibitory effect so that mucociliary function stopped totally within 20 min. with 5.0 mg/ml vadocaine solution. Both diphenhydramine and hydroxyzine totally stopped the ciliary activity during 20 min. with concentrations of 2.5 mg/ml and 1.0 mg/ml, respectively. Locke‐Ringer solution used as a control did not cause any change in the CBF. These results suggest that the antihistamines diphenhydramine and hydroxyzine are more ciliostatic than the antitussives dextromethorphan and vadocaine on the rat tracheal cilia in vitro. The results suggest further in vivo studies. The used photoelectric detection method proved to be suitable for evaluating drug effects on the CBF of respiratory mucosa.