bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of Hepatic Microsomal Drug Metabolism in Rats by Five Calcium Antagonists
Authors: Mäenpää Jukka , Ruskoaho Heikki , Pelkonen Olavi
Published: March 2009

Abstract:The effects of five calcium antagonists, verapamil, diltiazem, nifedipine, darodipine and isradipine, on rat liver microsomal drug metabolismin vitroandin vivowere studied. All compounds prolonged hexobarbital‐induced sleeping time in a dose‐dependent manner (doses 3.0 and 30.0 mg/kg, except nifedipine 0.3 and 3.0 mg/kg) and inhibited cytochrome P450‐dependent N‐demethylation of aminopyrinein vitroin rat liver microsomes. The incubation of all compounds with microsomes resulted in the apparent formation of formaldehyde, suggesting either N‐ or O‐demethylation. Diltiazem, isradipine and darodipine gave rise to a type I spectral change. Nifedipine seemed to produce a type II spectral change. A spectrum of verapamil changed from a type I to a type II as concentration increased. These results indicate that all calcium antagonists studied interact with P450 and arein vitroinhibitors of microsomal drug metabolism in the rat and the inhibition brings out pharmacokinetic drug‐drug interactionsin vivo.
Long‐Term Effect of Antidepressant Drugs and Electroconvulsive Shock (ECS) on Cortical α1‐Adrenoceptors Following Destruction of Dopaminergic Nerve Terminals
Authors: Nowak Gabriel
Published: March 2009

Abstract: The effect of repeated treatment with imipramine, citalopram and ECS on the density of α1‐adrenoceptors in the cerebral cortex of rats with a dopaminergic lesion was studied. Imipramine and citalopram produced α1‐upregulation in normal animals but not in animals with a dopaminergic lesion. On the other hand, ECS, produced such an effect in both normal and lesioned rats. Our results indicate that the investigated drugs (imipramine, citalopram) and ECS induce α1‐up‐regulation via different mechanisms, and that the effect of these drugs depends on intact dopaminergic nerve terminals.
Pharmacodynamics of BAY K 8644 Alone and in Combination with Dobutamine in the Isolated Rabbit Heart
Authors: Sørensen Else Vigholt , Pedersen Ole Lederballe
Published: March 2009

Abstract:The haemodynamic effects of the Ca‐agonist BAY K 8644 alone and in combination with the selective β‐1‐adrenoceptor agonist dobutamine were studied in the isolated rabbit heart. BAY K 8644 produced a concentration‐dependent increase in contraction amplitude and shortening velocity, oxygen consumption and heart rate. In combination with a small fixed concentration of dobutamine (40 nM), Bay K 8644 produced similiar alterations. When Bay K 8644 was infused at a fixed concentration (38 nM), dobutamine likewise produced similiar increments in contraction amplitude, shortening velocity and heart rate, whereas oxygen consumption was considerably augumented. Both BAY K 8644 and dobutamine showed definite positive inotropic effects in the isolated rabbit heart. Combination of the two drugs did not yield a stronger positive inotropic effect than that seen on single drug administration, and oxygen consumption was even increased.
Preferential Inhibition of Mouse Hepatic Coumarin 7‐Hydroxylase by Inhibitors of Steroid Metabolizing Monooxygenases
Authors: Kojo Anneli , Honkakoski Paavo , Järvinen Päivi , Pelkonen Olavi , Lang Matti
Published: March 2009

Abstract: Etomidate, metomidate and metyrapone, all potent inhibitors of steroid metabolizing monooxygenases, inhibit preferentially coumarin 7‐hydroxylase (COH) amongst several liver microsomal monooxygenase activities from control and pyrazole‐treated D2 mice in vitro. SKF‐525A, an inhibitor of phenobarbital‐inducible monooxygenase activities has a much weaker effect on COH than the other three drugs, even though COH is a phenobarbital‐inducible enzyme. Treatment of mice with eto‐ and metomidate decreases the microsomal COH also in vivo while the other activities remained unchanged (with the exception of 7‐ethoxycoumarin O‐deethylase (ECDE) in case of metomidate). Despite of the decrease in COH no parallel decrease in the amount of microsomal P450Coh (P450 isoenzyme highly active in the 7‐hydroxylation of coumarin) could be found in dot immuno‐binding analysis. These data suggest that among several liver microsomal P450 isoenzymes, metyrapone, eto‐ and metomidate interact preferentially with the P450Coh and that eto‐ and metomidate may alter selectively the catalytic properties of P450Coh leading to decreased enzyme activity. Two different Ks‐values could be found for all three drug in their binding to microsomal cytochrome(s) P450. Based on substrate binding spectra, potassium ferricyanide treatment does not dissociate the complex between reduced P450 and metomidate and does it only partly for etomidate. Furthermore potassium ferricyanide treatment of microsomes does not increase COH after in vivo treatment of mice with eto‐ and metomidate. These data further suggest that the complex between P450Coh and eto‐ and metomidate may be particularly strong and independent from the redox state of the haem iron.
Intramuscular Atropine in Elderly People: Pharmacokinetic Studies Using the Radioreceptor Assay and Some Pharmacodynamic Responses
Authors: Kentala Erkki , Kaila Timo , Kanto Jussi
Published: March 2009

Abstract:The pharmacokinetics (radioreceptor assay, RRA) and some clinical effects of atropine were studied in 7 elderly gynaecological surgery patients. The RRA measures only the pharmacologically active isomer of atropine, 1‐hyoscyamine. Following a single 0.01 mg/kg intramuscular (M. deltoideus) injection, a very fast rate of absorption was found with mean peak serum concentration occurring after only 13 min. The reason for this could be either a preferential tissue uptake of the 1‐form or the injection site or both. The elimination half‐life was 2.27 hr. Only 23.1% of the given drug was excreted in urine in 24 hr as a pharmacologically active form. The clinical effects (heart rate rise, subjective sedation and antisialogogue effect) were seen after only 30 min. This somewhat faster appearance of clinical effects than in previous studies can be due to the injection site. The sedative effect of the drug is clear and long lasting in elderly people.
Effects of (‐)15‐Deoxyspergualin on Pancreatic Islet B‐Cell Function in Vitro and on the Development of Diabetes after Multiple Low Dose Streptozotocin Administration
Authors: Strandell E. , Andersson A. , Groth C.‐G. , Sandler S.
Published: March 2009

Abstract: The effects of (‐)15‐deoxyspergualin (15‐DS), a newly described immunosuppressive drug, have been investigated on diabetes induced in mice treated with multiple low‐dose streptozotocin (multiple SZ). Male C3D2F1 mice were treated with either intraperitoneal injections of saline or 15‐DS (2.5 mg/kg body weight) for a total of 10 days, starting during the first day of SZ administration (5 days; 40 mg/kg body weight). On day 14, 15‐DS‐treated animals were still normoglycaemic, whilst on day 21 there was only a partial reduction in the hyperglycaemia compared to that found in the saline treated animals receiving SZ. 15‐DS did not prevent hyperglycaemia in the long run (day 35‐63). Furthermore, morphological examinations of pancreatic glands suggested that the insulitis in the pancreatic islets was delayed in the 15‐DS‐treated animals. In control experiments mice were treated with 15‐DS+ the vehicle for SZ. This regimen did not hamper the glucose homeostasis of the animals. In vitro effects of 15‐DS were also examined. Isolated islets from C3D2F1 mice were cultured at different concentrations of 15‐DS (0.1‐10.0 mg/l). After one week in culture, islet insulin release, islet insulin and DNA content were measured. The islets looked fluffy after culture at the higher 15‐DS concentrations (4.0‐10.0 mg/l) and at 10 mM almost all of the islets disappeared. A dose‐dependent reduction of glucose‐stimulated insulin release could also be seen. In other experiments islets were exposed to SZ and subsequently cultured in the presence of 0.5 mM 15‐DS, however, 15‐DS could not prevent the reduction in insulin release due to SZ exposure. Since 15‐DS influences macrophage functions, the presently observed protective effects against the multiple SZ‐treatment could reflect a reduced local interleukin‐1 production in the islet vicinity. Alternatively, a lowered interleukin‐1 secretion could prevent the activation of other immune cells involved in the destruction of B‐cells.
Factors Involved in Absorption of Organic Mercuric Compounds from Rat Small Intestine: Comparative Study with Mercuric Chloride in Situ
Authors: Endo Tetsuya , Nakaya Shozo , Kimura Ryohei
Published: March 2009

Abstract: A correlation between absorption of organic mercuric compounds and their molecular weight or lipophilicity was investigated by the perfusion of rat small intestine. The intestine was perfused for 1.0 hr at different osmolality and different pH with buffers containing 10−4 M organic mercuric compounds, methyl mercuric chloride (MMC), phenyl mercuric chloride (PMC), p‐chloromercuribenzoic acid (PCMB) and p‐chloromercuriphenylsulfonic acid (PCMBS). The order of absorption of these compounds at several osmolalities and pHs (MMC>PMC>PCMB>PCMBS) was inversely correlated to their molecular weight. The increase in pH decreased markedly the absorption and n‐octanol/water partition coefficient of PCMB, and it decreased scarcely those of MMC, PMC and PCMBS. The order of the coefficients at each pH was as follows; PMC>MMC>PCMB>PCMBS, in disagreement with the order of absorption. These results suggest that the molecular weight is more important factor in the intestinal absorption of organic mercuric compounds than the lipophilicity.
The Effect of Toluene Exposure for up to 18 Months (78 Weeks) on the (Ca2+/Mg2+)ATPase and Fluidity of Synaptosomal Membranes Isolated from Rat Brain
Authors: Edelfors Sven , Ravn‐Jonsen Andree
Published: March 2009

Abstract:The effect of toluene on the central nerve system was studied by using rat brain synaptosomal membranes asin vitroandin vivomodels. The activity of Ca2+/Mg2+ATPpase and the membrane fluidity were determined. Short‐term exposurein vivoto 500 p.p.m. of toluene had an inhibitory effect on the enzyme studied whereas long‐term exposure to toluene caused an increased activity. Exposure to toluene had no effect at all on the membrane fluidity. Thein vitroexperiment showed an effect of toluene on both parameters. The alteration in the enzyme activity and membrane fluidity was parallel in the exposed animals as well as those of control. Our results show that long‐term exposure to toluene affects nerve cell membranes by other mechanisms than those observed underin vitroconditions.
Dopamine D1 and D2 Receptors Visualized in MPTP Treated C57 Mice by in Vitro Autoradiography: Lack of Evidence of Receptor Modifications in Parkinsonian Mice
Authors: Camps Montserrat , Ambrosio Santiago , Ballarin Montserrat , Reiriz Julia , Blesa Rafael , Mahy Nicole
Published: March 2009

Abstract: The effect of the neurotoxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) on D1 and D2 dopamine receptors was assayed using in vitro quantitative autoradiography. D1 receptor subtype was labeled using 1 nM of 3H‐SCH 23390 and D2 receptor subtype was labeled using 0.4 nM of 3H‐spiroperidol. The results are compared to the effect of MPTP on the striatal levels of dopamine and its metabolites, in BL C57 mice. While 2 and 5 doses of MPTP 30 mg/kg/day intraperitoneally reduced the content of striatal dopamine and its metabolites, no modifications were detected in D2 receptor subtype in any cerebral area studied. However, D1 receptors were reduced in the substantia nigra 24 hr after the last of 2 doses, but not later. We suggest a compensatory mechanism of the surviving dopaminergic neurones as well as the participation of spare receptors. This would explain the lack of receptor modification after the lesion obtained as seen by the striatal reduction of dopamine and metabolites content, after MPTP administration.
Effects of Long‐Term Aldrin Administration on Seizure Susceptibility of Rats
Authors: Castro V. L. S. S. , Palermo‐Neto J.
Published: March 2009

Abstract:The effects of long‐term administration of sub‐convulsive doses of aldrin, an organochlorinated pesticide, on seizure susceptibility of rats were studied. Results show that treatment with the pesticide made the rats more susceptible to sound‐induced seizures; an increment in post‐seizure depression time after maximal electroschock administration was also observed in aldrin‐treated animals. Aldrin administration displaced the control dose‐response curves constructed for amphetamine and pentylenetetrazol to the left and right, respectively; no differences were detected between control and aldrin‐treated rats for strychnine, picrotoxin or 3‐mercaptopropionic acid. The results, discussed in the light of the effects of aldrin on biogenic amines or on the electrophysiology of neurones suggested an involvement of both noradrenergic and alteration excitability of the CNS with the observed increments on seizure susceptibility.
Effects of Diethyldithiocarbamate and Tetraethylthiuram Disulfide on Zinc Metabolism in Mice
Authors: Sørensen Jens Ahm , Andersen Ole
Published: March 2009

Abstract: Chronic alcoholics with cirrhosis often develop symptoms of zinc deficiency. Tetraethylthiuram disulfide (TTD) is metabolized to two molecules of diethyldithiocarbamate (DDC). DDC chelates divalent metal ions, including zinc, by forming highly lipophilic neutral bis(dithiocarbamate)‐metal complexes. DDC could therefore enhance the intestinal zinc uptake or increase the rate of zinc excretion. Accordingly, treatment of alcoholism with TTD could either aggravate or alleviate zinc deficiency. The present study investigated effects of DDC and TTD on intestinal zinc uptake and on the rate of zinc excretion in mice. When given as very high single oral doses, DDC and TTD increased the intestinal uptake of a single oral dose of zinc. When added to the diet and administered in lower doses, closer to those administered to humans for treatment of alcohol abuse, both compounds were without effect on the rate of excretion of the body's zinc stores. In a long‐term experiment, where 65Zn was administered in the drinking water, these doses of TTD and DDC reduced the whole‐body retention of 65Zn. No treatment changed the organ distribution of zinc in any of the experiments. In conclusion strong indications emerge from the present study that TTD treatment of alcoholism is more likely to reduce the intestinal zinc absorption than to enhance it as has been suggested by other authors. Thus, the widely used experimental model using single oral exposure to metal and chelator conceivably may give erroneous results, when used to predict effects of prolonged exposures.
Psychomotor, Respiratory and Neuroendocrinological Effects of a μ‐Opioid Receptor Agonist (Oxycodone) in Healthy Volunteers
Authors: Saarialho‐Kere Ulpu , Mattila Mauri J. , Seppälä Timo
Published: March 2009

Abstract:Psychomotor performance related to driving and occupational skills was measured double‐blind and cross‐over in 9 healthy volunteers before and 1.5, 3 and 4.5 hr after intramuscular injection of oxycodone (0.13 mg/kg), oral diphenhydramine (100 mg) and placebo. The effects of oxycodone on performance peaked at 1.5 hr when it prolonged reaction time and impaired vigilance, attention, body balance and coordination of extraocular muscles. The subjects assessed themselves mentally slow, muzzy and impaired by performance on visual analogue scales still 3 hr after injection. Critical flicker discrimination was impaired and some respiratory depression still present at 4.5 hr after administration. Oxycodone elevated plasma prolactin at 1.5 and 3 hr while growth hormone levels remained unaffected. We conclude that the profile of psychomotor decrement produced by this μ‐opioid agonist closely resembles that of agonist‐antagonist analgesics.
Effect of Plasma Protein Binding on Kinetics of PN 200‐110 in the Isolated Perfused Rat Heart
Authors: Machard Brigitte , Chaumet‐Riffaud Philippe D.
Published: March 2009

Abstract:The myocardial accumulation and elimination pharmacokinetics of PN 200‐110 (PN) were investigated in the single pass isolated perfused rat heart by two methods. A direct method, radioactivity measurement in myocardial tissue after various perfusion times, and an indirect method, concentration determination in coronary effluent, by fractionary collection of samples, during infusion and elimination periods. Both methods showed that the myocardium could be considered as a one‐compartment model with regard to PN pharmacokinetics. The perfusion with a modified Krebs‐Ringer (MKR) solution containing 1 nM of (±)PN 200‐110 and [3H]‐(+)PN 200‐110 as radioactive tracer, led to an accumulation of about 61.4 fmol·mg−1myocardial tissue at steady‐state. The effect of protein binding on the uptake and pharmacokinetic parameters of PN has been investigated in this isolated perfused heart (IPH) model. Binding of PN decreased as a function of increasing bovine serum albumin (BSA) levels in the perfusion solution. As a matter of fact, the mean steady state myocardial concentration of PN was decreased by 42.9, 56.2, 76.5, 83.9 and 95.5% for respectively, 1, 2.5, 6, 10 and 40 g·l−1of BSA. In the same way, the free fraction, the apparent volume of distribution (Vd) and the distribution and elimination half‐lives were decreased. On the contrary, the elimination rate constant was increased.
Stimulation by Oestradiol of the Urinary Excretion of Perfluorooctanoic Acid in the Male rat
Authors: Ylinen Markku , Hanhijärvi Hannu , Jaakonaho Jaana , Peura Pekka
Published: March 2009

Abstract:The urinary excretion of perfluorooctanoic acid (PFOA) was studied in male Wistar rats after castration and oestradiol administration as well as in intact females and males. During the first 24 hr females excreted 72±5% (N = 6) of a single intraperitoneal dose of PFOA (50 mg/kg) in urine whereas the intact males excreted only 9±4% (N = 6). After castration followed by oestradiol administration (500 μg/kg every 2nd day for 14 days), the males excreted PFOA in urine in similar amounts as the females (68±14% at 24 hr, N = 10). Oestradiol treatment of non‐castrated males produced similar results (61±19% at 24 hr, N = 10). Also castration without oestradiol administration significantly enhanced the renal PFOA excretion, but not as effectively as oestradiol treatment. After 96 hr, the concentration of PFOA in serum of intact males was 17‐40 times higher than in the serum of other groups. PFOA was similarly bound by the proteins in the serum of females and males. Phase II metabolism of PFOA was not shown either in males or females.
Effect of Pinacidil on Sympathetic Neuroeffector Transmission in Rabbit Blood Vessels
Authors: Nedergaard Ove A.
Published: March 2009

Abstract:The effects of pinacidil on vascular sympathetic neuroeffector transmission were studied. Pinacidil (3 × 10−7‐3 × 10−4M) inhibited the contractions of rabbit isolated pulmonary artery evoked by nerve stimulation. This was the case both in the absence and presence of cocaine plus corticosterone. The inhibition reached a steady state and was reversible. Pinacidil (10−5‐3 × 10−4M), in the absence or presence of cocaine plus corticosterone, markedly enhanced the3H‐overflow evoked by electrical‐field stimulation of the artery preloaded with3H‐noradrenaline (3H‐NA). The enhancement was dependent on frequency (1‐30 Hz) in a complex manner. Phentolamine (3 × 10−6M), but not rauwolscine (10−6M) prevented the enhancement. Pinacidil (10−4M) did not antagonize the α‐methylnoradrenaline‐induced inhibition of3H‐overflow evoked by stimulation. Pinacidil (10−5‐3 × 10−5M) in a non‐competitive manner antagonized the contractions of isolated aorta elicited by noradrenaline (3 × 10−9‐3 × 10−5M), phenylephrine (2 × 10−8‐3 × 10−4M), adrenaline (10−9‐3 × 10−5M), histamine (10−6‐6 × 10−4M), serotonin (10−8‐10−4M), and potassium (10−3M). Pinacidil (10−6‐3 × 10−4M) and methacholine (3 × 10−8‐10−6M) relaxed aorta preconstricted with noradrenaline (10−7M). The relaxation caused by pinacidil was not dependent on the presence of endothelial cells, while that seen with methacholine was. Pinacidil (3 × 10−5‐3 × 10−4M) reduced the accumulation of3H by aorta incubated with3H‐NA (10−8M). It is concluded that pinacidil predominantly is a direct acting vasodilator. Furthermore, pinacidil probably does not inhibit presynaptic inhibitory α2‐adrenoceptors.
Anti‐Ischaemic Effects of Indomethacin and Ketamine on Hippocampus Neurones in Mongolian Gerbils
Authors: Petersen Erling N.
Published: March 2009

Abstract: Bilateral occlusion of the carotid arteries of Mongolian gerbils for 10 min. resulted in a consistent pattern of degeneration of hippocampal CA1 neurones. Administration of the non‐competitive NMDA antagonist ketamine (100 mg/kg intraperitoneally) 30 min. before the occlusion almost entirely prevented degeneration of CA1 neurones. Indomethacin 5 mg/kg intraperitoneally had no influence on the degeneration, either administered 30 min. before or 15 min. after occlusion. The production of prostaglandins from the NMDA receptor stimulation does not seem to be crucial for the development of the ischaemic lesions at least in the hours immediately following occlusion. Indomethacin did not reduce the anti‐ischaemic effect of ketamine in the doses presumably necessary to reduce the increase in intracranial pressure induced by ketamine.
A Study of the Possible Mechanisms Underlying the Convulsant Actions of a Linear Expanded Xanthine
Authors: Collins G. G. S. , Anson J.
Published: March 2009

Abstract:The actions of a mixture of the 4‐ and 9‐chloro derivatives of the linear expanded xanthine 5,7‐diethyl‐2‐chloroimidazo[4,5‐g]quinazoline‐6,8 (5H,7H)‐dione (chloro‐DCQD) on the isolated olfactory cortex slice of the rat have been investigated. Chloro‐DCQD evoked a slowly‐developing depolarization which intensified over a drug application period of at least 4 min. A pharmacological investigation of the response showed that it was not mediated by blockade of potassium channels or activation of voltage‐gated sodium channels, by a stimulant action at receptors to γ‐aminobutyric acid (GABA), excitatory amino acids or acetylcholine, or by antagonism of adenosine receptors. Chloro‐DCQD (2.5 mM) potentiated responses evoked by N‐methyl‐D‐aspartate (NMDA), L‐aspartate and L‐glutamate, probably by overcoming the magnesium ion block of the ion channel of the NMDA receptor complex. Chloro‐DCQD (2.5 or 5 mM) also increased pyramidal cell excitability and abolished GABA‐mediated postsynaptic inhibition but did not affect the excitability of, or neurotransmitter release from, the terminals of the lateral olfactory tract. Chloro‐DCQD competitively antagonized the inhibitory actions of adenosine on the olfactory cortex. These effects are consistent with the reported convulsant actions of chloro‐DCQD.
Membrane Actions of Ethanol on Rabbit Sino‐Atrial Node Studied by Voltage Clamp Method
Authors: Kotake H. , Hirai S. , Nawada T. , Kurata Y. , Watanabe M. , Hisatome I. , Hasegawa J. , Mashiba H.
Published: March 2009

Abstract:Electrophysiological effects of ethanol on rabbit sino‐atrial node were studied by means of the double‐microelectrode voltage clamp method. In spontaneously beating preparations, ethanol (above 1%) decreased the maximum rate of depolarization of the action potential. Furthermore, 3% ethanol produced a significant decrease in the action potential amplitude, the action potential duration at 50% repolarization and the rate of the diastolic depolarization. Of the current systems, voltage clamp studies showed that ethanol reduced the slow inward current, the time‐dependent potassium outward current and the hyperpolarization activated inward current. These observations indicate that ethanol does not have an effect on a single current system, but directly modifies the spontaneous discharge of sino‐atrial node pacemaker cells due to a reduction of the time‐dependent current systems.
Administration of Activated Charcoal or Sodium Polystyrene Sulfonate (KayexalateTM) as Gastric Decontamination for Lithium Intoxication: An Animal Model
Authors: Linakis James G. , Lacouture Peter G. , Eisenberg Marc S. , Maher Timothy J. , Lewander William J. , Driscoll James L. , Woolf Alan D.
Published: March 2009

Abstract: To determine whether sodium polystyrene sulfonate (SPS; KayexalateTM) is effective in decreasing the absorption of lithium (Li) and to test the assumption that Li is poorly adsorbed by activated charcoal, 130 mice were administered an orogastric dose of LiCl (250 mg/kg) followed immediately by orogastric SPS (10 g/kg, SPS Group), activated charcoal (6.7 g/kg, AC Group), or water in an equivalent volume (Control Group). Subgroups of each of the 3 groups were sacrificed at 1, 2, 4 and 8 hr after treatment and serum analyzed for Li concentration. Statistical analyses revealed no overall difference between the AC Group and the Control Group. However, the SPS Group differed from both the Control and the AC Group at each time interval, with Li concentrations significantly lower in the SPS Group. These results demonstrate that: 1) SPS, in this study, effectively reduced serum Li concentrations in an in vivo model, and 2) activated charcoal did not.
Metabolic Interaction Between Endogenous Methanol and Exogenous Ethanol Studied in Human Volunteers by Analysis of Breath
Authors: Jones A. W. , Skagerberg S. , Yonekura T. , Sato A.
Published: March 2009

Ethanol was administered to 5 healthy volunteers by intravenous infusion to maintain a constant blood‐alcohol concentration (BAC) of about 0.8 mg/ml (17.4 mmol/1) for 3‐4 hr. Before starting the infusion and at 15 min. intervals thereafter, we analysed end‐expired air by a highly sensitive gas chromatographic method. The presumed concentrations of ethanol and methanol in blood were estimated indirectly from measurements in the breath. The liquid/air partition coefficients of methanol were determined for whole blood, plasma, water, and cornoil when dilute solutions were equilibrated at 34° and 37°. The results at 37° were 2709 ± 165, 3400 ± 86, 2948 ± 221 and 44.5 ± 6.3 for whole‐blood/air, water/air, plasma/air and corn‐oil/air respectively. During infusion of ethanol, the concentrations of endogenous methanol in blood rose from being between 0.4‐0.8 mg/1 to reach between 1.2‐3.4 mg/1 with a substantial inter‐subject variation in rate of increase. Our results confirm the existence of endogenous methanol in human blood and breath and demonstrate that the concentrations present can rise to abnormally high levels when the body is flooded with exogenous ethanol.
Effects of α‐Adrenoceptor Active Drugs, Prostaglandin F2α and Vasopressin on Cystic and Hepatic Arteries of Pig and Man
Authors: Vagianos C. , Sjöberg T. , Andersson K.‐E. , Steen S.
Published: March 2009

Human and pig cystic and pig hepatic arteries were suspended in tissue baths and the effect of α‐adrenoceptor selective drugs, prostaglandin F2α (PGF2α) and vasopressin were investigated. Prazosin fulfilled the criteria for competitive antagonism in concentrations 10‐9‐10‐7 M. The pA2‐values were 9.53 in human cystic, 9.74 in pig cystic, and 9.57 in pig hepatic artery. Rauwolscine had no significant effect in the different arteries. In human cystic artery noradrenaline had significantly (P<0.05) higher Emax and pEC50‐values (135% of the preceding K+‐induced contraction and 6.4, respectively) compared with pig cystic (106% and 5.7, respectively) and pig hepatic artery (116% and 5.9, respectively). Vasopressin had no effect in the cystic arteries, whereas it had a high potency (pEC50 was 8.5) but low intrinsic activity (Emax was 14%) in pig hepatic artery. Prostaglandin F2α had a significantly higher Emax in human than in pig arteries. No differences were found in pEC50‐values. This study indicates a similarity in pharmacological characteristics of some vasoactive drugs especially between pig cystic and hepatic arteries. If this is also true in man, the easily obtainable cystic artery can be used for screening the effect of drugs on the hepatic artery.
Chronic Zimeldine Administration to Cats: Sustained Increase of Serotonergic Effect as Measured with Sleep Parameters
Authors: Sommerfelt Liv
Published: March 2009

Sleep effects of oral administration of the serotonin uptake inhibitor zimeldine to cats on 15 consecutive days was measured. On administration days 8 and 15 REM sleep and PGO activity were significantly reduced. The amount of SWS‐2 was not changed for the whole group, but a subgroup with low baseline values showed an increase during zimeldine administration. A REM sleep rebound was observed on withdrawal day 2, and NREM sleep PGO activity was increased on withdrawal day 5. The results indicate an increased serotonergic inhibition of PGO wave activity and REM sleep during chronic administration of zimeldine.
Influence of Paracetamol and Acetylsalicylic Acid on the Toxicokinetics of Toluene
Authors: Löf Agneta , Wallén Maria , Hjelm Ewa Wigaeus
Published: March 2009

To study the influence of paracetamol and acetylsalicylic acid on the toxicokinetics of toluene, 2 groups of 10 male volunteers were exposed to toluene vapor (3.25 mmol/m3, 4 hr) at two different exposure occasions: toluene alone and toluene+analgesics. Solvent concentrations in blood and hippuric acid concentrations in urine were measured during the exposure period and 3 hr after exposure. The concentration of toluene in blood increased after ingestion of paracetamol or acetylsalicylic acid, as compared to the control exposure. The ingestion of paracetamol significantly increased the area under the blood concentration versus time curve (P<0.05) and the apparent blood clearance was significantly reduced (P<0.05) after ingestion of paracetamol but not after ingestion of acetylsalicylic acid. No statistically significant differences in the urinary excretion of hippuric acid were found.
Effect of o,p'‐DDD on thein VivoIncorporation of3H‐Thymidine into DNA: Evidence for Induced Cell Proliferation in the Mouse Lung
Authors: Lund B.‐O. , Busk L. , Brandt I. , Hellman B.
Published: March 2009

The effects of o,p'‐DDD on the DNA synthesis in the C57B1 mouse lung and liver were studied. As determined by3H‐thymidine incorporation into DNA, a selective increase in the lung DNA synthesis (+59%) was observed 2 days after a single intraperitoneal injection of 100 mg/kg o,p'‐DDD. Microautoradiography showed that the incorporated3H‐thymidine was confined to a restricted number of heavily labelled cells, presumably proliferating type II cells. At the most, a 9 times higher rate of cell proliferation was observed in the lung 4 days after an intraperitoneal injection of 500 mg/kg o,p'‐DDD. Using mouse lung or liver S‐9 as activating system, no mutagenic activity of o,p'‐DDD was detected in the Ames test. The induced cell proliferation may indicate a tissue‐selective promotor activity of o,p'‐DDD in the mouse lung.
Relation of Ca++Accumulation and Lipid Peroxidation with CCI4‐Induced Toxicity in the Rat Liver
Authors: Yamamoto Hiro‐aki
Published: March 2009

The relationship between lipid peroxidation and Ca++content in liver and hepatic cellular disruption was studied in 24 hr‐fasted rats. Microsomal lipid peroxidation of livers in rats treated with a single dose of 16 mg or 96 mg CCI4/kg was significantly increaed by 22% or 49% as measured by the diene conjugation technique. Ca++content of liver microsomes in rats treated with 96 mg CCI4/kg was significantly increased by 20%, while the Ca++content in rats treated with 16 mg CCI4/kg was not changed. On the other hand mitochondrial Ca++content was tremendously increased in both rats treated with 16 mg and 96 mg CCI4/kg. Furthermore, when the activity of plasma glutamic pyruvic transaminase (GPT), which is a liver‐specific enzyme, was investigated 3 hr after CCI4treatment, hepatotoxicity was evident in rats treated with 96 mg/kg but not evident in rats treated with 16 mg/kg. These results indicate that there was a good correlation between the microsomal Ca++content and the hepatic cellular disruption but no correlation between the microsomal lipid peroxidation and the hepatic cellular disruption as measured by the diene conjugation.
A Double‐Blind Placebo Controlled Study of Healthy Volunteers Given a Subcutaneous Disulfiram Implantation
Authors: Johnsen Jon , Stowell Allan , Stensrud Tore , Ripel Åse , Merland Jerg
Published: March 2009

A study was carried out to elicit information of the pharmacological effect of implanted disulfiram (DS). Healthy volunteers were randomized to either of two groups; six were given 1 g DS implant and six subjects placebo (PL) implants. Each participant was subjected to one intravenous ethanol challenge before, and six intravenous ethanol challenges as well as one oral ethanol challenge after the implantation. No clinical signs of disulfiram‐ethanol reactions (DER) were observed. The intravenous challenges did not result in any significant differences between pre‐ and post‐implantation values for blood acetaldehyde concentrations in the DS group, and these values were not significantly different from the corresponding values in the PL group. However, somewhat higher blood acetaldehyde concentrations were recorded after an oral ethanol dose (0.8 g/kg) in the DS group. In a longitudinal study with oral ethanol challenges after implanted DS, one of three healthy volunteers had a significant higher blood acetaldehyde concentration three weeks after the implantation, while no such tendency was found in any subject tested earlier or later in the post‐implantation period. The blood acetaldehyde levels after oral challenges were, however, far too low to produce a DER.
Comparison of the Distribution of Three Bisphosphonates in Mice
Authors: Mönkkönen Jukka , Koponen Hanna‐Maija , Ylitalo Pauli
Published: March 2009

The distribution of approximately equipotent doses of14C‐labelled clodronate (0.1 mmol/kg), etidronate (0.1 mmol/kg), and amidronate (0.015 mmol/kg), and also an equimolar dose of amidronate (0.1 mmol/kg), was studied in mice by measuring the14C‐activities in various tissues up to 360 days after a single intravenous injection. With the higher dose of amidronate the distribution could be, however, monitored only for 7 days because of the toxicity of the drug. The results indicate that there are major differences in the deposition of the bisphosphonates into soft tissues, while the disappearance from plasma and incorporation into bone are quite similar in terms of percentage of dose per g of tissue. However, the binding capacity of bone for clodronate and etidronate is many times greater than that for amidronate expressed as nmol of the drug per g of tissue. Amidronate deposits in the spleen and liver of mice, when injected in saline, whereas clodronate and etidronate do not. This agrees with the suggestion that amidronate, but not the other two, can interfere with the mononuclear phagocyte system of spleen and liver.
The Protective Effect of Sulfite on Menadione‐ and Diquat‐Induced Cytotoxicity in Isolated Rat Hepatocytes
Authors: Sun Yueping , Cotgreave Ian A. , Lindeke Björn , Moldéus Peter
Published: March 2009

Menadione and diquat cause toxicity in isolated hepatocytes. The toxicities of both menadione and diquat are primarily due to redox cycling and consequent oxidative stress. Menadione toxicity, however, has another component as the compound also possesses alkylating and oxidating properties allowing it to interact directly with cellular nucleophiles. Sulfite afforded considerable protection of isolated rat hepatocytes against the toxicity of menadione. This protective effect of sulfite may have several components. Sulfite effectively competed with glutathione (GSH) for conjugation with menadione, sparing intracellular GSH which may continue to detoxify reactive oxygen species formed through menadione redox cycling. The menadione sulfite conjugate undergoes much slower redox cycling than both menadione and the menadione glutathione conjugate. Sulfite also showed some degree of protection of hepatocytes from the toxicity of diquat. Diquat is a “pure” redox cycling agent and the protective effect of sulfite may involve the liberation of GSH from GSSG by sulfitolysis. This would again bolster intracellular GSH levels allowing further GSH‐dependent detoxification of reactive oxygen species through cellular GSH peroxidases. In conclusion, our data illustrate the potential of inorganic sulfite to support the intracellular detoxification function of GSH, both against reactive electrophilic metabolites and against agents undergoing redox cycling.
TCDD Inhibits the Support of B‐Cell Development by the Bursa of Fabricius
Authors: Nikolaidis Efstathios , Brunström Björn , Dencker Lennart , Veromaa Timo
Published: March 2009

The toxic effects produced by 2, 3, 7, 8‐tetrachlorodibenzo‐p‐dioxin (TCDD) and its congeners include inhibition of lymphoid development. We have previously found an inhibition of B‐cell development in the bursa of Fabricius of chick embryos treated with TCDD congenersin ovo. In the present study, the bursae of ten‐day‐old chick embryos were removed and cultured on filter paper for 24 hr in media with or without TCDD or 3,3′,4,4′‐tetrachloroazoxybenzene (TCAOB). Following culture, the bursae were transplanted onto the chorioallantoic membrane (CAM) of ten‐day‐old eggs of the same strain or of a strain expressing a different B‐cell surface alloantigen. After 5 days on the CAM the number of B‐cells was determined or the grafts were sectioned for subsequent immunohistochemistry. Results were as follows: 1) A lower number of lymphoid cells (dose dependent) was observed in the TCDD‐treated transplants amounting to 40–50% of that in the controls at 10‐9M TCDD. Higher concentrations of TCDD compromised survival of the grafts. A single concentration of TCAOB (10‐8M) was tested, resulting in a lymphoid cell number of 60% of that of the controls. 2) The bursal epithelium showed relatively normal development even in cases where B‐cell development was affected. 3) Lymphoid cells in the grafted bursae originated from the embryo of the host egg. These findings suggest that the TCDD congeners had a direct effect on the bursa of Fabricius, leading to an inhibition of lymphoid development. It is likely that the microenvironment is affected by these compounds, thus resulting in a decrease in the attraction of stem cells and/or in the capacity to induce proliferation of the colonizing cells.
Cardiovascular Consequences of Organophosphorus Poisoning and of Antidotes in Conscious Unrestrained Rats
Authors: Bataillard A. , Sannajust F. , Yoccoz D. , Blanchet G. , Sentenac‐Roumanou H. , Sassard J.
Published: March 2009

The cardiovascular effects of two organophosphorus, paraoxon and soman, as well as of antidotes advocated in the treatment of these intoxications have been investigated using a computerized analysis of arterial blood pressure in conscious unrestrained rats. Intravenous administration of paraoxon as well as of soman produced a marked, sustained and dose‐related increase in blood pressure associated with a bradycardia. Pyridostigmine, a quaternary carbamate, neither altered blood pressure nor heart rate. Benzodiaxepines, such as diazepam or loprazolam, and atropine induced a dose‐dependent tachycardia while pralidoxime decreased heart rate. A complete therapeutic scheme including the intravenous administration of pyridostigmine 10 min. before a postpoisoning therapy made of pralidoxime, diazepam and atropine induced a transient tachycardia, which was followed, after a return to control values, by a second and more stable tachycardia concurrently to a slight hypertension. Postpoisoning therapy alone suppressed the pressor effect of soman within a few minutes after its administration. Afterwards, this therapy reduced the importance of the cardiovascular effects produced by soman. Pyridostigmine pretreatment decreased the protection afforded by postpoisoning therapy in soman‐intoxicated rats. These results show that postpoisoning therapy with pralidoxime, diazepam and atropine has a noteworthy efficacy against cardiovascular manifestations of soman intoxications in the rat.
Effects of Positive Inotropic Drugs on the Frequency of Contraction of the Isolated Atria: Influence of Dose Regimen and Age
Authors: Sørensen Else Vigholt
Published: March 2009

The dose‐activity relationship of various positive inotropic drugs has been investigated in the spontanously beating right atria of the rat. The influence of dose regimen and age has been evaluated. There is a significant difference between the maximal response of single and cumulative dose experiments with amrinone (P<0.05) and dobutamine (P<0.001) in animals aged 2 months and in dopamine (P<0.001) in animals aged 4 months. The maximum response is lowered significantly with age for isoprenaline with single (P<0.05) and for dopamine and dobutamine with cumulative dosing (P<0.001). In the single dose study the response is achieved within 4 min. for isoprenaline, noradrenaline, dobutamine, xamoterol and amrinone, but not until after 14 min. for prenalterol. It is concluded that both age and methods used in the study of pharmacodynamics are important. Thus when comparing effects the use of the same method and tissue from rats of the same age is necessary.
Increased Serum Selenium Levels in Patients under Corticosteroid Treatment
Authors: Marano G. , Fischioni P. , Graziano C. , Iannone M. , Morisi G.
Published: March 2009

The normal serum and tissue levels of many micronutrients are remarkably affected by the therapeutical administration of several substances. In the present study, we have evaluated the modifications of serum selenium levels in different groups of patients under corticosteroid treatment. Such therapy was significantly associated with increased serum selenium levels, with a dose‐dependent relationship in subjects treated with methylprednisolone. The reasons for this association are unknown. However, a reduced renal excretion of selenium, due to the mineralcorticoid activity of the corticosteroids, can be inferred.
α1 (but not α2)‐Adrenoceptor Agonists in Combination with the Dopamine D2 Agonist Quinpirole Produce Locomotor Stimulation in Dopamine‐Depleted Mice
Authors: Eshel Galia , Ross Svante B. , Kelder Diana , Edis Lil E. M. , Jackson David M.
Published: March 2009

Mice were premedicated with reserpine and α‐methyl‐p‐tyrosine to deplete stores of dopamine (DA) (and other neurotransmitters) and to stop DA (and noradrenaline (NA)) synthesis. In DA‐depleted mice, the mixed α1/α2 agonist clonidine potentiated locomotor stimulation induced by a low dose of apomorphine as measured in automated activity cages. Clonidine and the slightly αl‐selective agonist ST587, but not ST91, an α‐agonist which does not readily cross the blood brain barrier, produced marked stimulation when combined with the selective D2 agonist quinpirole. The D1 ‐selective agonist SKF38393 also produced marked excitation when combined with quinpirole. All the selective agonists, bar quinpirole which in some cases produced a significant locomotor stimulation, were relatively inactive when given alone. A “blind” observational analysis of the animals challenged with clonidine plus quinpirole indicated an increase in sniffing, rearing and shaking behaviour. In contrast, observation of the animals challenged with SKF38393 plus quinpirole indicated increased sniffing, rearing and biting and, in one case, increased grooming behaviour. Clonidine did not produce excitation (in automated cages) when combined with the selective D1 agonist SKF38393. The excitation produced by clonidine plus quinpirole was blocked by the selective D2 antagonist raclopride but not by the selective D1 antagonist SCH23390. The stimulation was also blocked by the α1 antagonist prazosin but not by the α2 antagonists idazoxan or yohimbine. Biochemical analysis in the striata of mice challenged with clonidine plus quinpirole did not provide any obvious biochemical basis for the behavioural interaction. It is concluded that α1 receptor agonists in combination with D2 DA agonists can produce marked stimulation in DA depleted mice.
An Automated Method for the Determination of Nortriptyline and its Isomeric 10‐Hydroxylated Metabolites in Plasma by High Pressure Liquid Chromatography
Authors: Lundgren T. I. , Slørdal L. , Jæger R. , Whist J. E. , Aarbakke J.
Published: March 2009

A high pressure liquid chromatography assay for determination of the tricyclic antidepressant nortriptyline (NT) and its two major metabolites, Z‐ and E‐10‐Hydroxy‐NT, in plasma is described. Sample preparation included addition of internal standard and a single step extraction procedure. Run time was approximately 14 min. with a LC‐18, 5μ 250 × 4.6 mm column, a mobile phase consisting of aqueous ammonium: methanol: acetonitrile (0.8:6.2:93, v/v), and a flow of 1.3 ml/min. NT, Z‐ and E‐10‐OH‐NT, amitriptyline, Z‐ and E‐10‐OH‐AT and the internal standard desipramine, were adequately separated within this time span. In our laboratory, the assay has been employed mainly for pharmacokinetic and toxicologic studies in experimental animals at relatively high concentrations.
Pathophysiologic Effects of Anatoxin‐a(s) in Anaesthetized Rats: The Influence of Atropine and Artificial Respiration
Authors: Cook William O. , Iwamoto Gary A. , Schaeffer David J. , Carmichael Wayne W. , Beasley Val R.
Published: March 2009

The pathophysiologic effects of anatoxin‐a(s) from the cyanobacteriumAnabaena flos‐aquaeNRC‐525‐17 were investigated in anaesthetized adult male Sprague Dawley rats given the toxin by continuous intravenous infusion until death. Rats (n=6) pretreated with atropine sulfate (50 mg/kg) intraperitoneally survived significantly longer (P<0.05) than non‐atropinized rats (n = 6), suggesting that the muscarinic effects of anatoxin‐a(s) were important in the lethal syndrome. In contrast to rats only given toxin, rats that were pretreated with atropine had a decrease in heart rate and mean blood pressure that followed profound reductions in respiratory tidal and minute volume, suggesting that neuromuscular blockade of the muscles of respiration was the cause of death. Even when survival time of rats was increased by pretreatment with atropine, phrenic nerve amplitude increased, indicating a lack of a depressive effect of anatoxin‐a(s) on central mediation of respiration. Rats (n=3) continuously ventilated during toxin infusion survived a dose more than 4 fold greater than a consistently lethal dose of the toxin. Thus, the cardiovascular effects of anatoxin‐a(s) alone could not account for the death of rats. Electromyographic activity recorded from the diaphragms of rats (n=5) during continuous toxin administration revealed an increase in muscular electrical activity that became more random and finally decreased prior to death, suggesting a toxin‐induced neuromuscular blockadein vivowhich ultimately was the cause of death of the anatoxin‐a(s) dosed rats.
Disposition of3H‐Aflatoxin B1in Mice: Formation and Retention of Tissue Bound Metabolites in Nasal Glands
Authors: Larsson Pia , Hoedaya Wientarsih Ietje , Tjälve Hans
Published: March 2009

Whole‐body autoradiography with3H‐labelled aflatoxin B1(3H‐AFB1) in C57B1‐mice showed a pronounced accumulation and retention of radioactivity in some nasal glands. At long survival intervals the labelling of the nasal glands was much higher than that of the liver. Experimentsin vitroshowed a capacity of the nasal glands to form tissue‐bound3H‐AFB1‐metabolites. Incubations in the presence of glutathione decreased the levels of tissue‐bound3H‐AFB1‐metabolites both in the liver and in the nasal glands, but the decrease was more pronounced in the former than in the latter tissue. The3H‐AFB1‐metabolite‐binding to the nasal glandsin vitrowas inhibited by the cytochrome P‐450‐inhibitor metyrapone and by CO‐ and N2‐atmospheres indicating a cytochrome P‐450‐dependent bioactivation of the AFB1in these glands. Cytochrome P‐450 was shown to be present in the glands although at a much lower level than in the liver. The glands in the nose, which were shown to have this AFB1‐metabolizing capacity, were the lateral nasal gland (Steno's gland) situated ventrally and laterally to the maxillary sinus and the large group of glands in the lateral nasal wall ventrally to the ostium of the maxillary sinus. Our results also indicated an AFB1‐metabolizing capacity of the serous glands which are present in the anterior part of the nasal septum.