bluuebunny/crossref_metadata_2025 huggingface dataset:
Central Nervous Effects of the Convulsant Protein Canatoxin *
Authors: Carlini C. R. , Gomes C. , Guimaraes J. A. , Markus R. P. , Sato H. , Trolin G.
Published: July 2010

Abstract:Some pharmacological‐toxicological effects of canatoxin, a toxic protein purified from the seeds ofCanavalia ensiformishave been studied in mice and rats. The most obvious effect, a lethal tonic convulsion, was generally produced 10–15 min. after intravenous injection of 2–3 mg/kg of the highly purified protein (mol. wt. 88,000). After intraperitoneal, intramuscular or subcutaneous administration the convulsion produced by the same toxin dosis occurred within 24 hours. A spinal transection at the midthoracic level did not abolish the convulsions of the hindlimbs while destruction of the medulla below this level completely blocked the convulsions of the hindlimbs. The convulsions of the head and forelimbs were unaffected by these surgical pre‐treatments. The toxic protein did neither affect the isolated skeletal muscle nor did it potentiate nerve impulse induced contractions. The convulsive effect of canatoxin was potentiated by reserpine and attenuated by phenobarbital, diazepam, methenesine and also by haloperidol and spiroperidol. The total concentration of brain and spinal cord neurotransmitters seemed to remain unchanged after subconvulsive and convulsive doses of canatoxin. In the conscious rat the toxic protein did not change the blood pressure except for a shortlasting hypertensive response observed immediately before the onset of the convulsions. The heart frequency was lowered at subconvulsive and convulsive dosis but no effect was seen on the frequency of the rat isolated right atria exposed to high doses of canatoxin. The body temperature was lowered by a convulsive dosis of the toxic protein. The purified toxin did not show any haemagglutinating property or haemolytic phospholipase A2‐like activity. The results strongly suggest a central nervous site for the action of canatoxin. However, if the effects are produced by the intact protein or not as well as its exact mode of action, remain unexplained.
Organic Acid Transport to the Blood from the Corpus Striatum, the Thalamus and the Cerebellum of the Rat
Authors: Grabowska‐Andén Maria , Andén Nils‐Erik , Bárány Ernst , Magnusson Anneli
Published: July 2010

Abstract:Conscious rats were given intracerebral injections by preplaced microsyringes. The injectates were 0.3–0.5 μl of125I‐ and131I‐o‐iodohippurate. One hour after injection the isotopes present in the unopened cranial cavity were measured by gamma spectrometry. Some animals received 200 mg/kg probenecid intraperitoneally and this reduced the rate of absorption from injectates into the corpus striatum to 65.7×12.6% of control; from injectates into the cerebellum to 57.1×9.8% of control. Dye injections showed that injections into the cerebellum did not remain in the parenchyma, in contrast to injections into the corpus striatum or thalamus. Probenecid was also given as 2.9% solution, pH 7, mixed with the iodohippurate in the microsyringe. It had no effect on injections into the cerebellum, reduced the rate of absorption from the corpus striatum to 80.9×3.2% of controls and that from the thalamus to 88.3×2.2%. The results indicate parenchymal probenecid‐sensitive transport of iodohippurate from the corpus striatum and thalamus but failed to settle the matter for the cerebellum.
Cardiovascular Effects of Intramuscular or Inhaled Terbutaline in Asthmatics
Authors: Buch Jan , Bundgaard Allan
Published: July 2010

Abstract:8 stable asthmatics were at random given placebo, 0.125 mg, 0.25 mg, 0.5 mg and 1 mg terbutaline intramuscularly or 2.5 mg as inhalation. Systolic time intervals, echocardiographic parameters and peak expiratory flow (PEF) were measured. Maximal circulatory and respiratory response was obtained after 0.5 mg and 0.25 mg, respectively. The circulatory effect of 2.5 mg inhalated terbutaline equalled 0.125 mg given intramuscularly, while this dosage elicited maximal bronchodilator effect. Thus, nebulized terbutaline has only a minimal circulatory effect, and even the intramuscular dosages were without dramatic circulatory side effects.
The Effect of Two Different Buffers on the High Affinity3H‐Ethylketocyclazocine and3H‐SKF10047 Binding to Guinea Pig Brain Membranes
Authors: Grynne Birthe H. , Maurset Atle R. , Hobnen Aase T. , Enger Mette
Published: July 2010

Abstract:In vitroμ and δ opioid receptor binding is known to be influenced by ions. High affinity3H‐SKF10047 and3H‐ethylketocyclazocine binding sites are found in brain membranes and postulated to be similar to μ opioid receptor binding. To investigate this postulate, we have studied how the high affinity binding of3H‐SKF10047,3H‐ethylketocyclazocine, a tritiated μ agonist, μ antagonist and δ agonist is altered when the radioreceptor binding assay incubation buffer is changed. The binding of3H‐ethylketocyclazocine and the μ antagonist (3H‐naloxone) is highest in isotonic HEPES buffer, while the binding of the μ (3H‐dihydromorphine) and δ (3H‐D‐ala‐D‐leu‐enkephalin) agonist is highest in hypotonic Tris‐HCl buffer.3H‐SKF10047 binding is similar in the two buffers. The inhibition of3H‐ethylketocyclazocine,3H‐SKF10047 and tritiated μ and δ opioid ligands by seven unlabeled ligands is then compared in the two buffers. Morphine chloride is a more potent inhibitor of3H‐ethylketocyclazocine binding and tritiated μ ligand in hypotonic Tris‐HCl buffer than in isotonic HEPES buffer. The potency of naloxone, nalorphine, SKF10047, D‐ala‐D‐leu‐enkephalin, cyclazocine and phencyclidine in inhibiting3H‐ethylketocyclazocine binding is independent of the buffer system. None of the seven unlabelled substances change potency with buffer change when inhibiting the 1.2 nM3H‐SKF10047 binding. In sum our results show that 1 nM3H‐ethylketocyclazocine binding is influenced by buffer change in a manner very similar to μ ligand binding, while the 1.2 nM3H‐SKF10047 binding is only slightly influenced by buffer change and therefore different from μ ligand binding.
Cerebral Blood Flow Autoregulation during Acute Ethanol Intoxication in the Rat
Authors: Barry David I. , Hemmingsen Ralf
Published: July 2010

Abstract: Autoregulation of cerebral blood flow (CBF) was studied in anaesthetized rats during acute ethanol intoxication (blood alcohol concentration 2.5 to 3 g/l). For each rat an autoregulation curve was determined: 8–10 CBF measurements were made over the mean arterial pressure range 129 mmHg to 20 mmHg. MAP was raised above the resting level by angiotension II infusion, then lowered by controlled haemorrhage. In control rats, CBF autoregulation was demonstrated within the MAP range 129 mmHg to 70 mmHg: at lower pressure autoregulation was inadequate and CBF fell. In ethanol intoxicated rats CBF autoregulation was demonstrated within the MAP range 129 mmHg to 50 mmHg: at lower pressure CBF fell. Although the lower limit of CBF autoregulation was thus at an MAP 20 mmHg less than in control rats, this probably reflects suppression of cerebral metabolism, rather than an effect of ethanol on CBF autoregulation per se.
The Influence of Prazosin and Propranolol on Serum Lipids and Atherosclerosis in Standard Fed Pigs
Authors: Helgeland Anders , Eriksen Karin , Foss Per Olav , Nafstad Inger , Solberg Lars Aage , Tollersrud Svcrre
Published: July 2010

Abstract: The influence of prazosin and propranolol on serum lipids and atherosclerosis was evaluated in standard fed pigs during a nine months experimental period. The incidence and severity of atherosclerotic lesions was very low, and no difference could be observed neither between the two drugs nor between the drug groups and the placebo group. Prazosin and propranolol induced no marked change in the serum lipid profile. The results could be explained by the very low fat content, 3.6 per cent, in the present standard diet.
Naloxone‐Ethanol Interaction in Experimental and Clinical Situations
Authors: Nuotto E. , Palva E. S. , Seppälä T.
Published: July 2010

Abstract: The effect of naloxone on ethanol‐induced impairment of psychomotor performance was studied in a series of three placebo‐controlled, double‐blind trials. In all trials, two successive intravenous injections of naloxone (0.4 and 2.0 mg) were given at an interval of 0.5–1.5 hours. Cross‐over trials with healthy volunteers (n = 17) were performed in laboratory. In these conditions, naloxone alone had no effect on performance. Ethanol alone (1.0 and 1.5 g/kg) dose‐dependently induced nystagmus and impaired coordination, reactions, hand cooperation, body balance, flicker discrimination and extraocular muscle balance. When naloxone was given after ethanol, the first injection reduced slightly but significantly ethanol‐induced (1.5 g/kg) nystagmus, while the second injection did not enhance this counteraction any more. Other alcohol effects were not significantly antagonized by naloxone. The clinical part of the study, consisting of parallel groups of either naloxone (n = 11) or saline (n = 7) ‐treated alcohol‐intoxicated (mean blood alcohol concentration 2.9 mg/ml) out‐patients, most of them alcoholics, showed that no counteraction of alcohol inebriation (measured by clinical inebriation tests) was associated with the treatment with naloxone in the clinical situation either. Our results suggest that naloxone has no clinical significance in antagonizing ethanol intoxication. The inebriating effects of ethanol are not importantly mediated via central opioid mechanisms.
Sensory Irritation and Pulmonary Irritation by Airborne AUyl Acetate, AUyl Alcohol, and Allyl Ether Compared to Acrolein
Authors: Nielsen G. D. , Bakbo J. C. , Hoist E.
Published: July 2010

Abstract:The propene derivatives, allyl acetate, allyl alcohol, allyl ether, and acrolein were investigated for their property as sensory irritant in Ssc:CF‐1 mice. The concentration of the chemicals necessary to depress the respiratory rate by 50% (RD50) due to sensory irritation of the upper respiratory tract were 2.9, 3.9, 5.0 and 2.9 p.p.m., respectively. The potency of these propene derivatives varied very little for their concentration in air, in p.p.m., to depress the respiratory rate by 50%. However, when the potency is expressed in terms of thermodynamic activity acrolein was found to be 10 times more potent than the other propene derivates. This may be explained either by a higher reactivity of the carbon‐carbon double bond or the involvement of the aldehyde group in a secondary chemical binding. No secondary chemical binding can be invoked for allyl acetate, allyl alcohol or allyl ether. In general, the chemical structure CH2=CH‐CH‐O may be suspected to allow a molecule to act as a strong sensory irritant. The TLV's were predicted from the relation: TLV0.03 ± RD50 and were found to be 0.1, 0.1, 0.15, and 0.1 for allyl acetate, allyl alcohol, allyl ether, and acrolein, respectively. No pulmonary irritation was found at the concentration causing a 50% decrease in respiratory rate.
The Effects of Metformin Compared to the Effects of Phenformin on the Lactate Production and the Metabolism of Isolated Parenchymal Rat Liver Cell
Authors: Jailing Olaf , Olsen Christian
Published: July 2010

Abstract: The metabolic effects of metformin were compared to the effects of phenformin on isolated parenchymal liver cells from fed and fasted rats with ethanol or glycerol as the only substrate. Both biguanides caused a fall in the hepatic oxygen‐consumption, in the cellular ATP‐content and in the ATP/ADP‐ratio. The lactate production and the concentration‐ratios of lactate/pyruvate and of P‐hydroxybutyrate/acetoacet‐ate rose. The production rate of ketone bodies remained unchanged. This response was the same whether the hepatocytes were from fed or fasted rats and whether glycerol or ethanol was substrate. Only quantitative differences in the response on the biguanides were detected. The effects of the biguanides were dose dependent. Phenformin was ten times more potent than metformin. The same holds for their therapeutical potency. The findings indicate inhibition of the oxidative phosphorylation by both biguanides resulting in reduction of the cytoplasmic and the mitochondrial redox potentials causing enhanced lactate production. It is concluded that metformin excerts the same effects as phenformin on the hepatic metabolism, when the concentration ratio is about ten to one. Both biguanides give rise to elevated lactate production. This effect is highly increased when ethanol is present.
Is there any Evidence of β1‐Adrenoceptors Mediating Relaxation of Guinea‐pig Lung Parenchyma?
Authors: Johansson Lars‐Håkan , Persson Henry , Rosengren Evald
Published: July 2010

Abstract:We tried to find functional evidence for the existence of β1‐ and β2‐adrenoceptors in the isolated guinea‐pig lung parenchymal strip preparation, using potent and selective β1‐ and β2‐adrenoceptor stimulation. To obtain potent β1‐adrenoceptor stimulation the nonselective β‐adrenoceptor agonist isoprenaline was combined with a highly selective β2‐adrenoceptor antagonist ICI 118,551. Potent β2‐adrenoceptor stimulation was obtained by procaterol. Practolol (β1‐adrenoceptor antagonist) and ICI 118,551 were used as antagonists. ICI 118,551, 107mol/l, shifted the concentration response (C/R) curve of isoprenaline to a higher concentration range. The C/R curve of procaterol was shifted in the same way and to the same degree by this concentration of ICI 118,551. The C/R curve of isoprenaline was not further shifted after blockade with a combination of ICI 118,551, 10‐7mol/l, and practolol, 10‐6mol/l. However, in the trachea preparation, a tissue containing both β1‐ and β2‐adrenoceptors, there was a further shift of the C/R curve of isoprenaline to a higher concentration range after blockade with a combination of ICI 118,551 and practolol in the concentrations given above. In this preparation the shift of the C/R curve of procaterol was ten times greater than that of isoprenaline after blockade with ICI 118,551, 107mol/l. We conclude that it is possible to characterize small fractions of β1‐adrenoceptors coexisting with β2‐adrenoceptors with the technique used. Furthermore there is still no functional evidence of the existence of β1‐adrenoceptors in the lung parenchyma.:
Effect of Warfarin on ATP Content, Viability, Glycosylation and Protein Synthesis in Isolated Rat Hepatocytes
Authors: Gjerde Hallvard , Helgeland Liv
Published: July 2010

Abstract:The effect of warfarin on ATP content, viability and incorporation of labelled glucosamine and leucine into protein was studied in suspensions of rat hepatocytes. When incubated with warfarin the synthesis of total protein and glycoprotein was equally inhibited, and the viability and ATP content of the cells were also lowered. These observations suggest that warfarin is not an inhibitor of glycosylation of proteins in isolated hepatocytes, however, the presence of warfarin leads to reduced ATP content of the cells which causes a decrease in protein synthesis and viability.
On the Pharmacokinetics of Fenflumizole, a Novel Antiinflammatory Agent, after Single Oral Administration to Healthy Subjects
Authors: Midskov Carsten , Vinge Ellen , Andersson Karl‐Erik
Published: July 2010

Abstract: The disposition of fenflumizole, a recently developed imidazole derivative which inhibits prostanoid formation, was studied after single oral administration to eight healthy subjects. Fenflumizole was given in the doses 0.1, 1 and 2 mg/kg as an aqueous suspension. Plasma concentrations within the first 24 hrs were amenable to a two‐compartment open model and showed a rapid absorption with a half‐life of about 0.5 hr and peak concentrations in plasma after about 1 hr. The elimination phase became dominating after about 10 hrs with a half‐life of 14–15 hrs. Peak plasma levels and areas under the concentration‐time curves prior to onset of the elimination phase indicated a small reduction of the bioavailability with dose on comparison of the highest and the lowest dose (P<0.05) but for the whole observation period of 24 hrs no dose‐dependent bioavailability was revealed. The mean transit time in plasma ranged from 21 to 22 hrs. Two metabolites (demethylation products) were detected in both plasma and urine. Their plasma concentrations amounted to only about 5% of those of the parent compound, and they were rapidly eliminated. The total urinary recovery of the intact fenflumizole and the two metabolites was less than 0.1%0 of the given doses. The renal clearance of fenflumizole was estimated to about 0.02 ml/hr.
Perchloroethylene: Effects on Body and Organ Weights and Plasma Butyrylcholinesterase Activity in Mice
Authors: Kjellstrand P. , Holmquist B. , Kanje M. , Aim P. , Romare S. , Jonsson I. , Månsson L. , Bjerkemo M.
Published: July 2010

Abstract:The effects of continuous and intermittent inhalation of perchloroethylene (PCE) on plasma butyrylcholinesterase (BuChE) activity, organ weights, liver morphology and motor activity in mice (strain NMRI) were tested. PCE exposure increased plasma BuChE activity in a time‐ and concentration dependent manner in both sexes. The increase was statistically significant at 37 p.p.m. in animals continuously exposed for 30 days. BuChE increased approximately 1.5 times in females and 2.5 times in males after 120 days exposure to 150 p.p.m. After rehabilitation of animals exposed for 30 days to 150 p.p.m., BuChE levels returned to normal. Liver weight also increased in a time and concentration dependent manner. Both sexes exhibited significant liver enlargement at 9 p.p.m. The increase was about 2.3 in females and 1.9 in males after continuous exposure to 150 p.p.m. for 120 days. After rehabilitation (120 days) of animals exposed to 150 p.p.m. for 30 days, a 10% increase still remained. A decrease in body weight gain was seen in both sexes after exposure to concentrations above 75 p.p.m. Female kidney weight was slightly increased. No clear effect on spleen weight could be detected. When the same time‐weighted average concentration was used, intermittent exposure for 30 days had similar effects on liver weight and BuChE activity as continuous exposure, even when exposures lasted for only one hour per day. Liver cell morphology was changed after PCE exposure. The alterations could be observed already at 9 p.p.m. but disappeared after rehabilitation.
8‐Bromo‐cGMP Improves Energy State in Hypoxic Rat Atria
Authors: Laustiola Kai , Vuorinen Pauli , Metsä‐Ketelä Timo
Published: July 2010

Abstract:8‐bromo‐cGMP (1 × 10‐4M) was found to prevent the hypoxia‐induced decrease in creatine phosphate (CrP) and ATP in isolated rat atria. An increase in ADP was also seen after 8‐bromo‐cGMP treatment, while the AMP level remained unchanged. 8‐bromo‐cGMP administration resulted in a higher energy charge during the initial state of hypoxia. 8‐bromo‐cGMP did not affect heart rate or contractility during hypoxia. These results suggest that cGMP improves the energy state of the heart cell in hypoxia. The exact mechanism(s) of these effects is not known but an improvement of oxidative phosphorylation might, quantitatively, account for the changes.
Characterization of the Binding of3H‐Norzimeldine, a 5‐HT Uptake Inhibitor, to Rat Brain Homogenates
Authors: Hall Håkan
Published: July 2010

Abstract:The binding of radiolabelled norzimeldine, a potent selective 5‐HT reuptake inhibitor, to rat brain homogenates is described.3H‐Norzimeldine binds to a site with high affinity (KD = 10.5 nM) in a saturable manner (Bmax= 15.4 pmol/g wet weight in the cerebral cortex). The number of binding sites in the various regions of the brain parallels the capacity of the 5‐HT reuptake mechanism. Drugs that inhibit the reuptake of 5‐HT are also potent inhibitors of the3H‐norzimeldine binding, as are the tricyclic antidepressants, which are non‐specific inhibitors of the noradrenaline and the 5‐HT reuptake. Lesioning experiments using DSP4 (a NA neurotoxin) and p‐chloroamphetamine (a 5‐HT neurotoxin) suggest that the binding site is located on the presynaptic 5‐HT nerve terminal, although a small component of the binding may be to noradrenergic uptake sites as well.
Liquid Chromatographic Assay for CSF Catecholamines Using Electrochemical Detection
Authors: Seppala T. , Scheinin M. , Capone A. , Linnoila M.
Published: July 2010

Abstract:A liquid chromatographic assay for noradrenaline (NA), dopamine (DA), and 3,4‐dihydroxyphenylacetic acid (DOPAC) in human and monkey cerebrospinal fluid (CSF) is described. The limits of sensitivity vary between 0.1–0.3 pmol/ml of each catechol. Within‐day precision as indicated by mean coefficient of variation (CV) of five days varied between 8.0–14.8 for NA (3.0–0.1 pmol/ml), 6.9–27.4 for DA (6.0–0.1 pmol/ml), and 4.1–17.6 for DOPAC (30–1 pmol/ml). Between‐day precision (CV) was estimated to be 12.3, 14.9 and 16.6 for 4 pmol/ml of NA, DA and DOPAC, respectively. The method was reproducible enough for reliable quantitation of CSF free NA and DOPAC levels at physiological concentrations while the sensitivity for DA was too low to measure the free amine in less than 3 ml of human lumbar CSF. After acid hydrolysis total (free + conjugated) DA can, however, be quantified in CSF. Ranges for CSF NA and DOPAC levels were 0.13–2.0 and 0.43–14.6 pmol/ml in normal volunteers (n = 72), 0.19–3.19 and 0.7–7.09 pmol/ml in untreated chronic schizophrenic patients (n = 52), and 1.1–3.2 and 9.8–22.7 pmol/ml in rhesus monkeys (n = 8), respectively.
Chlorinated Paraffins: Effect of some Microsomal Enzyme Inducers and Inhibitors on the Degradation of 1‐14C‐Chlorododecanes to14CO2in Mice
Authors: Darnerud Per Ola
Published: July 2010

Abstract:The degradation of 1‐14C‐chlorododecanes to14CO2in C57B1 mice was studied. 1‐14C‐Chlorododecane‐injected mice were transferred to an all‐glass metabolism cage and the exhaled air was monitored for14CO2. Pretreatment with cytochrome P‐450 inhibitors resulted in a marked decrease in the rate of14CO2‐formation, when measured as peak14CO2‐exhalation rate (PER): After piperonyl butoxide pretreatment the degradation rate of a high‐chlorinated14C‐dodecane (PCDD II; 68% Cl w/w) to14CO2was 16% of control, and after metyrapone pretreatment 40%. It was also shown that piperonyl butoxide pretreatment decreased the rate of14CO2‐formation, and the amount of14CO2formed, in proportion to the chlorine content of four differently chlorinated dodecanes. The cytochrome P‐450 inducer phenobarbital moderately (PER 152%) increased the rate of14CO2‐formation from PCDD II, whereas 3‐methylcholanthrene and several technical grade chlorinated paraffins generally gave less or no inductive effects. Also the cumulative14CO2‐exhalation, measured during six hours (CE‐6), was inhibited and induced after the above pretreatments. The results indicate a cytochrome P‐450‐dependent degradation of C12‐chloroalkanes to14CO2in vivo. The degradationviacytochrome P‐450 seems to be relatively more important for higher chlorinated alkanes.
Effect of Sodium Diethyldithiocarbamate on Placental Passage and Foetal Distribution of Cadmium and Mercury in Mice
Authors: Jasim Suhair , Tjälve Hans
Published: July 2010

Abstract: The administration of sodium diethyldithiocarbamate to 18 day pregnant mice, which previously had been given 109Cd2+ or 203Hg2+ was found to result in increased levels of the metals in the foetuses, in comparison with mice given the 109Cd2+ or 203Hg2+ alone. The level of 109Cd2+ in some foetal tissues was increased 30–60 times. In the animals given 203Hg2+ 3–5 times higher concentrations were seen in most foetal tissues of the sodium diethyldithiocarbamate‐treated animals compared with animals not treated with this substance. Cadmium and mercury were shown to form highly lipophilic complexes with diethyldithiocarbamate and a facilitated transfer of these complexes through the placental membranes probably explains the increased uptake of the metals in the foetuses.
Effects of Acute Ketotic and Non‐ketotic Diabetes on the Myocardial Muscarinic Receptors
Authors: Bergh Claes‐Håkan , Ransnäs Lennart , Hjalmarson Åke , Waldenström Anders , Jacobsson Bo
Published: July 2010

Abstract:Myocardial membranes from rats rendered diabetic with streptozotocin were used to determine muscarinic receptors with5H‐quinuclidinyl benzilate. In the acute state of diabetes, four days after induction, the density of receptors were equal in controls, insulin (glucosuria) and non insulin‐treated (glucosuria and ketonuria) diabetic animals. In myocardial membranes from diabetic rats agonist binding to the muscarinic receptor was shifted to higher affinity than in controls. Computer modeling revealed that guanine nucleotides transformed agonist binding from two sites to a site of low affinity in controls. In membranes from insulin‐treated diabetic animals the shift to lower affinity occurred but two receptor sites remained. In non insulintreated membranes the nucleotides failed to exert any effect. Inhibition of adenylate cyclase by the muscarinic agonist oxotremorine was amplified in diabetic membranes. This indicates that the function of the inhibitory nucleotide binding protein (N1), as reflected by agonist binding to the receptor and adenylate cyclase inhibition, is sensitive to the hormonal status.
Failure of Amantadine and Bromocriptine to Counteract Alcoholic Inebriation in Man
Authors: Nuotto Esko , Mattila Mauri J.
Published: July 2010

Abstract:Oral amantadine 100 mg and bromocriptine 2.5 + 2.5 mg, alone and in combination with ethanol (1 g/kg), were investigated in two placebo‐controlled, double‐blind and cross‐over trials. In the first trial the psychomotor effects of amantadine and bromocriptine were compared to those of placebo, and in the second trial ethanol was added to the treatment. Bromocriptine lowered serum prolactin levels, thus confirming its absorption. Amantadine and bromocriptine alone had no psychomotor effects but unpleasant sensations, nausea and dizziness were reported after bromocriptine. Ethanol impaired performance in terms of impaired coordinative and reactive skills, lowered tapping speed, prolonged critical flicker interval and reduced gaze nystagmus angle (P<0.05 to 0.001; two‐way ANOVA). Subjectively, ethanol induced mental slowness, clumsiness and impairment of performance (P<0.05 to 0.001). Amantadine and bromocriptine failed to counteract any of these ethanol‐induced changes. It is concluded that in man, an acute dopaminergic activation by amantadine or bromocriptine does not significantly modify the psychomotor effects of ethanol.
Long‐term Effects of Two Antidepressants on Copulatory and Exploratory Behaviour in the Female Rat
Authors: Smith Lena A. C. , Meyerson Bengt J.
Published: July 2010

Abstract:The immediate and long‐term effects of antidepressant drugs on two different behaviours — copulatory and exploratory — were compared in hormone‐treated, ovariectomized rats. The drugs used were desmethylimipramine (DMI 2 and 5 mg/kg) and zimeldine (ZIM 5 and 25 mg/kg). The acute effects were studied 1–4 hours after drug injection, and the long‐term effects after four weeks of daily injections. The acute treatment with DMI and ZIM significantly suppressed the lordosis behaviour compared with that in saline‐treated controls. After long‐term administration of DMI, the 5 mg/kg dose of this drug was still able to inhibit the lordosis response, while the low dose of DMI and ZIM did not produce a significant effect after chronic administration. We suggest that subsensitivity to certain effects of the antidepressant drugs develops during the long‐term treatment.
Effects of Carbidopa on the Cerebral Accumulation of Exogenous L‐5‐Hydroxytryptophan in Mice
Authors: Magnussen Ib
Published: July 2010

Abstract:The concentration of L‐5‐hydroxytryptophan (5‐HTP) was measured in plasma and whole brain tissue from mice by use of high pressure liquid chromatography with fluorimetric detection after reaction with phthaldialdehyde. 5‐HTP was injected intraperitoneally and the rise in plasma and brain 5‐HTP concentrations was found directly related to the size of amino acid dose. Carbidopa, an extracerebral inhibitor of L‐aromatic amino acid decarboxylation, increased dose dependently the brain bioavailability of systemically administered 5‐HTP not only by peripheral enzyme inhibition, but also by inhibition of the decarboxylase activity within the blood‐brain barrier as indicated by a rise in the calculated brain/plasma 5‐HTP concentration ratio.
Effects of Acute Administration of 5‐Methoxy‐N,N‐dimethyltryptamine upon the Latency and Duration of Post‐decapitation Convulsions
Authors: Archer Trevor , Tandberg Bengt
Published: July 2010

Abstract:The effect of acute administration of rats with the 5‐hydroxytryptamine (5‐HT) agonist drug 5‐methoxy‐N,N‐dimethyltryptamine on the convulsions released by decapitation was examined. The postsynaptic agonist, 5‐methoxy‐N,N‐dimethyltryptamine, prolonged the latency and duration from the 0.5 mg/kg dose upwards. Methergoline, 2.0 mg/kg intraperitoneally injected immediately prior to 5‐methoxy‐N,N‐dimethyl‐tryptamine, caused some considerable blockade of the effects of the 5‐HT agonist on post‐decapitation convulsions (PDC's). Long‐term p‐chloroamphetamine (2 × 10 mg/kg) and p‐chlorophenylalanine (1 × 300 mg/kg) did not antagonise the 5‐methoxy‐N,N‐dimethyltryptamine induced changes of PDC's but, by themselves, prolonged PDC duration. The utility of the 5‐methoxy‐N,N‐dimethyltryptamine‐PDC method for studying 5‐HT receptor mechanisms may be worth considering.
Antidotal Treatment of the Acute Cardiovascular Toxicity of Verapamil
Authors: Strubelt O.
Published: July 2010

Abstract: Rats anaesthetized with pentobarbital and ventilated artificially were infused with 0.15 mg/kg/min. verapamil; without antidotal treatment, they died after 51.1 ± 7.1 min. The survival time more than trebled upon an additional infusion with calcium chloride, epinephrine, isoprenaline, orciprenaline or prenalterol and nearly doubled upon administration of a plasma expander. It was not increased, however, by treatment with angiotensin or atropine. The infusion of verapamil declined the arterial blood pressure by 75%, and heart rate, cardiac output and peripheral resistance by about 50%; in the ECG, sinus bradycardia followed by AV‐dissociation with nodal rhythm occurred. All antidotes that raised the lethal dose of verapamil increased the cardiac output. Calcium and the sympathomimetics with α‐adrenergic activity also counteracted the verapamil‐induced hypotension. Calcium did not influence the ECG alterations produced by verapamil, while the sympathomimetics restored the sinus rhythm or accelerated the nodal pacemaker. Calcium, epinephrine and isoprenaline also antagonized the strong decrease of left‐ventricular dp/dt max. induced by verapamil. In conclusion, calcium as well as sympathomimetic amines are potent antidotes against the cardiovascular toxicity of verapamil, the latter being superior to calcium in their ability to improve pacemaker activity and AV‐conduction.
Site and mechanism of the action of diuretics
Authors: Odlind Bo
Published: July 2010

Abstract:The mechanism of action of diuretics can be established by studying the molecular mechanism of action, the site of action within the nephron, and the relationship between the pharmacokinetics of the diuretic and its effect. The molecular mechanism of action is known for diuretic agents such as acetazolamide (carbonic anhydrase), theophylline (phosphodiesterase), digitalis glucosides (Na‐K‐ATPase), spironolactone (aldosterone antagonism) and dopamine (specific receptors?). The “receptor” for the clinically most important diuretics, i.e. loop diuretics, thiazides, and other potassium‐sparing diuretics is, however, unknown. It appears from recent studies of the ion transport in the dilating segment that there probably is a sodium‐chloride co‐transport in this segment and that loop diuretics specificly inhibit the active chloride transport. The main site of diuretic action is well established for the different groups of diuretics: carbonic anhydrase inhibitors act on the proximal tubulus, loop diuretics on the diluting segment, thiazides on the cortical diluting segment/distal tubulus, and potassium‐sparing agents on distal tubulus/collecting ducts. Moreover, some diuretics have additional tubular sites of action. It is also important to realize that other effects of diuretics, e.g. inhibition of the tubuloglomerular feedback mechanism or renal and extrarenal hemodynamic effects, can modify the tubular diuretic effect. Finally, the renal handling of diuretics is of importance to the diuretic effect by determining the concentration of the drug at the “receptor” sit (s). It is emphasized that knowledge of the different aspects of the mechanisms of action of diuretics is a prerequisite for rational use of diuretics, clinically as well as experimentally.
Saluretics and converting‐enzyme blockade in the treatment of resistant hypertension
Authors: Delin Krister , Aurell Mattias , Herlitz Hans
Published: July 2010

Abstract: Blockade of the actions of the renin‐angiotensin‐aldosterone axis by inhibition of the angiotensin‐converting enzyme with captopril is a new tool in the field of hypertension. As treatment with captopril makes pressure control volume‐dependent, the addition of a saluretic is considered the best choice if an additional hypotensive agent is needed. The reason for and experience of the use of captopril in combination with saluretics for treatment of severe hypertension is reviewed. Published results indicate that captopril alone is insufficient, but as many as a third of the patients with previously uncontrollable hypertension manage well when a saluretic is added. Only one in six remains uncontrolled despite the addition of several other hypotensive agents. These observations apply to both essential and secondary forms of hypertension.
Metabolic side effects of diuretics and β‐adrenoceptorblockers
Authors: Bengtsson Calle
Published: July 2010

Abstract:A review is made of the metabolic side effects of diuretics and β‐adrenoccptorblockers. The review is based on results from a population study. performed by the author, of women and on a survey of the literature. While diuretics give rise to hypokalemia, which may be of clinical importance, β‐adrenoceptorblockers tend to increase the serum potassium levels. This does not, however seem to be of clinical significance. Both diuretics and β‐adrenoceptorblockers increase serum uric acid levels, β‐adrenoceptorblockers inciease serum tryglycerides. which is not observed when diuretics are used. Total cholesterol in serum is usually not changed either by diuretics or by β‐adrenoceptorblockers. These drugs seem to have no influence on body weight when studied during long‐term treatment. A further deterioration of glucose tolerance may be expected in subjects with an initially impaired glucose tolerance when diuretics are administered, while results from studies on glucose tolerance in subjects taking β‐adrenoceptorblockers have been controversial. Diabetes miellitus seems to he more common umong subjects on diuretics as well as among subjects on β‐adrenoceptorblockers, but as yet it cannot be stated whether this is an effect of the antihypertensive drugs or of the hypertension per se or of some other factor or factors.
Treatment of congestive heart failure
Authors: Sjögren Andreas
Published: July 2010

Abstract:The past decade has improved our understanding of the pathophysiological mechanisms underlying the congestive heart failure syndrome. The same decade has seen a considerable expansion in modes of therapy for this syndrome. A review of the present forms of treatment is given.
Harmine–, LON–954– and 5–Hydroxytryptophan–induced Tremors in Rats Withdrawn from Ethanol
Authors: Gothóni P.
Published: July 2010

Abstract:The tremors induced by harmine, LON–954 (N–carbamoyl–2–(2,6–dichlorophenyl)acctamidine hydrochloride) and 5–hydroxytryptophan (5–HTP) were studied in control rats and in rats withdrawn for 16–48 hrs from 6 to 9 days' ethanol administration. The frequencies and the intensities of the tremors were determined electronically. In control rats the frequency spectra of the tremors induced by harmine (20 mg/ kg) and LON–954 (10 mg/kg) showed a narrow peak frequency at about 10 Hz. Atropine (1.2 mg/kg) altered neither the frequency nor the intensity of these tremors. 5–HTP (50 mg/kg) when given 3.5 hrs after iproniazid (100 mg/kg) induced tremor with peak frequencies at 6–7 Hz and 12 Hz. In ethanol–withdrawn rats treated with harmine or LON–954 the frequency analysis of tremor revealed a narrow peak frequency at about 12 Hz, which was neither the characteristic frequency of ethanol withdrawal tremor (6 Hz) nor that of harmine or LON–954 (10 Hz). The intensity of both harmine– and LON–954–induced tremor was significantly increased in ethanol–withdrawn rats. The ethanol–withdrawn rats were markedly sensitized to the effect of iproniazid + 5–HTP, shown by deaths. The peak frequencies of this tremor were the same as those in control rats. The results suggest that harmine–induced tremor involves a dopaminergic–5–HT'ergic imbalance and the tremor induced by LON–954 a dopaminergic–cholinergic imbalance in the brain. The tremor in ethanol–withdrawn rats seems to be mediated by alterations in the activity of the cerebral 5–HT'ergic system
Local Toxicity of Different Drugs after Intramuscular or Intralipomatous Injection in Pigs: Serum Concentrations after Three Different Formulations of cis(Z)–Clopenthixol
Authors: Svendsen Ove , Blom Lars , Aaes‐Jørgensen Tove , Larsen Jens‐Jørgen
Published: July 2010

Abstract: Findings made by computerized tomography scanning of pelvis of patients suggested that the majority of injections intended to be intramuscular in fact are delivered in the fat tissue. This finding has raised the question what difference it makes when drugs are injected intramuscularly or intralipomatously. We have studied local toxicity after intramuscular or intralipomatous injection of different drugs in pigs, which have a subcutaneous layer of fat comparable to that of man. The pigs were killed 1, 3, 7 or 14 days after injection of antibiotics, vitamins, neuroleptics, diazepam, digoxin, pentazocine, sulphadimidine and vehicles. The tissues at the injection site were examined macro– and microscopically. In another series of experiments an aqueous or two different oily preparations of the neuroleptic drug cis(Z)–clopenthixol were given intramuscularly or intralipomatously to pigs and a series of blood samples were taken for drug level determination. The tissue examinations showed that all drugs causing local muscle damage after intramuscular injection caused considerably less extensive damage with a faster regeneration after intralipomatous injection. The pharmacokinetic study showed that there was virtually no difference between plasma–concentration–time curves after intramuscular or intralipomatous injection. Our findings indicate that intralipomatous injection of irritating drugs is better tolerated than intramuscular injection since intralipomatous injection causes less local toxicity. Our findings also suggest that the pharmacokinetics are not different. However, further studies are required to substantiate whether the findings are of general relevance
Effects of Solvent Exposure on Testosterone Levels and Butyrylcholinesterase Activity in Mice
Authors: Kjellstrand P. , Bjerkemo M. , Adler‐Maihofer M. , Holmquist B.
Published: July 2010

Abstract:In female and male mice the effect of exposure to trichloroethylene (TCE) seen at the lowest concentration is an increase in liver weight. The activity of plasma butyrylcholinesterase (BuChE) increases even more than the liver weight at corresponding concentrations, but only in the males. Depletion of testosterone through castration or destruction of the pituitary gland or hypothalamus, are the only other ways to experimentally induce corresponding increases in BuChE. Plasma BuChE activity increase was found to be a common reaction after exposure to TCE, perchloroethylene, chloroform, methylenechloride and carbon tetrachloride and also after exposure to ethanol. Other solvents such as toluene, xylene, benzene and 1,1,1–trichloroethane had little or no effect on BuChE activity. Normal and castrated male mice were continuously exposed for one month to 150 p.p.m. TCE. The increase in BuChE activity after the exposure was of the same magnitude as the increase seen after castration. BuChE activity in castrated males was not further increased by TCE exposure. Administration of testosterone with osmotic minipumps for 13 days almost restored the normal testosterone and BuChE levels in castrates. The effect of TCE exposure on BuChE activity in these animals was the same as on normal males. Testosterone levels were not influenced by the TCE exposure in normal males or in castrates given testosterone. No sex hormone binding globulins (SHBG) could be detected in the mice. BuChE activity changes induced through solvent exposure are therefore neither directly nor indirectly (through SHGB) due to effects on testosterone. The results from these animal experiments do not support the epidemiological findings of decreased testosterone levels in humans exposed to solvents
Lack of Hepatotoxicity after Long–term Administration of Cyanamide in Rats: A Histological and Biochemical Study
Authors: Obach R. , Rives A. , Vallés J. M. , Menargues A. , Pruñonosa J. , Vallés J.
Published: July 2010

Abstract: An experimental long–term hepatotoxicity study of cyanamide in Sprague–Dawley and Wistar rats has been carried out. After six months oral administration of cyanamide (2,7 and 25 mg/kg/day) no significant histological changes have been observed in the liver. Similarly, a one year intraperitoneal administration of 8 and 16 mg/kg/day has not induced any hepatic change. Specifically, no inclusion bodies in any cyanamide treated rat have been detected. Moreover, hepatic biochemical parameters have shown no significant impairment of hepatic function at doses used in human therapy (0.5–1 mg/kg)
Kinetic Models for Plasma Disappearance of Insulin in Normal Subjects
Authors: Thorsteinsson Birger , Fugleberg Steen , Feldt‐Rasmussen Bo , Binder Christian
Published: July 2010

Abstract: Three theoretical kinetic models for plasma disappearance of insulin were examined in six normal men. The models allowed for the existence of non–saturable and/or saturable mechanisms. Constant infusion of porcine insulin at different rates was used to achieve different levels of steady state plasma insulin concentrations, while normoglycaemia was secured by a glucose clamp technique. Appropriate validation procedures demonstrated that one of the three models was superior to the others in describing the relationship between the exogenous insulin infusion rate Iexand the steady state plasma insulin concentration C: Iex = – Iend + k2/(k3 + C), where Iend is the endogenous post–hepatic insulin delivery rate. Thus, only saturable mechanism(s) could be demonstrated. The median value of k2 (the maximal insulin disappearance rate) and k3 (the plasma insulin concentration at which the insulin disappearance rate is half maximal) were 7.31 nmol–min.–1 and 3.89 nmol 1–1. The median value of k2/k3 (the clearance rate of insulin for infinitesimal plasma insulin concentrations) was 25.0 ml–kg–1–min.–1. Thus, at physiological levels of plasma insulin concentrations the metabolic clearance rate of insulin is higher than insulin clearance estimates previously reported in studies based on the assumption of first order kinetics
Oxotremorine Acts as a Partial Nicotinic Agonist on Cultured Chick Myotubes
Authors: Häggblad J. , Eriksson H. , Heilbronn E.
Published: July 2010

Abstract:Oxotremorine, a compound widely used as a muscarinic agonist, was found to inhibit binding of125I–α–bungarotoxin to chick myotube nicotinic acetylcholine receptors, IC50 = 79 ± 5 μM. Oxotremorine also induced a d–tubocurarine sensitive influx of86Rb in the myotubes (EC50 = 50 ± 15 μM). Comparative ion–flux studies with carbachol suggested a partial agonist mode of action of oxotremorine
A Comparison of Effects of BAY K 8644 and CGP 28392, Dihydropyridines with Ca Agonistic Properties, on Spontaneous Mechanical Activity in Rat Portal Vein: Modification of Effect by Ultraviolet Radiation
Authors: Mikkelsen Erich O. , Nyborg Niels C. B. , Jakobsen Preben
Published: July 2010

Abstract: The effect of CGP 28392 and BAY K 8644 was studied on isolated portal veins from male Wistar Kyoto rats. BAY K 8644 and CGP 28392 induced a concentration dependent increase in spontaneous mechanical activity in low but not in high concentrations. The portal vein was more sensitive to the effect of BAY K 8644 than to that of CGP 28392. In Ca free medium the increasing effect of BAY K 8644 and CGP 28392 on the mechanical activity was abolished and restored by readdition of calcium. Nifedipine abolished the augmenting effect of BAY K 8644 and CGP 28392 on mechanical activity. Ultraviolet radiation (UVR) depressed the effect of BAY K 8644 but had no effect on mechanical activity induced by CGP 28392. BAY K 8644 and CGP 28392 degradate slowly under influence of UVR; BAY K 8644 was far more resistant to the destroying effect of UVR than CGP 28392. The results indicate that both BAY K 8644 and CGP 28392 increase the spontaneous mechanical activity in rat portal vein by enhancing Ca influx. The effect of BAY K 8644 differs from that of CGP 28392 by being sensitive to UVR; this action seems not to be due to a direct UVR destroying effect of the substances, but rather to a BAY K 8644 induced sensibilisation of the tissue to UVR
Cytochrome P‐450‐dependent Fragmentation of DNA in Reconstituted Membranes
Authors: Luthman Holger , Ingelman‐Sundberg Magnus
Published: July 2010

Membrane vesicles containing various forms of rabbit liver microsomal cytochromes P‐450 and NADPH‐cytochrome P‐450 reductase were found to degrade plasmid DNA in an NADPH‐requiring reaction. When cytochrome P‐450 was replaced by cytochrome b5, only a negligible extent of DNA disintegration occurred. The complete inhibition of the process by hydroxyl radical scavengers, superoxide dismutase and catalase, indicated an iron‐catalyzed Haber‐Weiss reaction for the generation of hydroxyl radicals that subsequently react with the nucleic acid.
Anticholinergic Activity in the Serum of Patients Receiving Maintenance Amitriptyline or Doxepin Therapy
Authors: Aaltonen L. , Syvälahti E. , Iisalo E. , Peltomäki T.
Published: July 2010

The anticholinergic activity in serum of depressive patients receiving amitriptyline (50–300 mg/day) or doxepin (50–225 mg/day) was measured using a radioreceptor assay. In this method the membrane suspension prepared from rat brain was able to bind the potent muscarinic antagonist, quinuclidinyl benzilate. Using atropine as a standard, the antimuscarinic activity of several compounds can be measured in the serum of patients receiving drugs with anticholinergic effects or side‐effects. The steady state serum levels of amitriptyline and doxepin and their desmethylated metabolites, nortriptyline and desmethyldoxepin were measured by radioimmunoassay in the same serum samples. The antimuscarinic activity in serum measured as atropine equivalents was 2.7 ± 0.4 (S.E.M.) ng/ml in amitriptyline patients and 1.1 ± 0.2 ng/ml in doxepin patients. There was a highly significant correlation (P<0.001) between amitriptyline (r = 0.92) and nortriptyline (r = 0.79) concentrations and serum antimuscarinic activity. The correlation was less clear, although statistically significant for doxepin (r = 0.42, P<0.05) and desmethyldoxepin (r = 0.58, P<0.01). The better correlation between serum drug levels and antimuscarinic activity in amitriptyline than in doxepin patients is probably due to the higher affinity of amitriptyline and its desmethylated metabolite to muscarinic receptors with the doses used in the present study. The method may have clinical applications e.g. in evaluation of excessive anticholinergic activity in patients.