bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Hypoxia on the Metabolism and Hepatotoxicity of Carbon Tetrachloride and Vinylidene Chloride in Rats
Authors: Siegers Claus‐Peter , Horn Werner , Younes Maged
Published: July 2010

The metabolism of vinylidene chloride (VDC) and carbon tetrachloride (CCl4) was investigated by measuring the removal of the compounds from the atmosphere of a closed exposure system occupied with male rats. Hepatotoxicity was evidenced in the same rats by determining serum enzyme activities of the aminotransferases (GOT, GPT) and sorbitol dehydrogenase (SDH) before, at the end of the exposure time and 24 hrs later. Control rats exposed to VDC concentrations up to 2000 p.p.m. showed only slight increases of serum aminotransferase‐ and SDH‐activities, which were not at all observed under hypoxic conditions. Hypoxia evoked a small, but significant reduction of the VDC metabolism at 500 p.p.m., but not at 2000 p.p.m. exposure concentration. In contrast to VDC CCl4‐metabolism (150 p.p.m.) was increased under hypoxia and consequently hepatotoxicity was aggravated.
Ibuprofen, Pharmacokinetics and Pharmacodynamics in the Isolated Rabbit Heart
Authors: Askholt J. , Nielsen‐Kudsk F.
Published: July 2010

Myocardial pharmacokinetics and dynamic effects of the non‐steroidal antiinflammatory drug ibuprofen were studied in isolated, spontaneously beating and retrogradely perfused rabbit hearts. Both myocardial uptake and disposition of ibuprofen showed two‐compartment characteristics, which possibly reflects extracellular and intracellular binding sites. Initial and terminal kinetic half‐lives were about 0.6 and 13.4 min., respectively. Vdβwas about 82 ml/g myocardial tissue. Stepwise increased ibuprofen concentrations from 30 to 160 μg/ml in the Krebs‐Henseleit perfusion liquid produced a progressive increase in coronary flowrate up to 178%, which then decreased somewhat at higher concentrations. Preliminary observations showed a direct relaxing effect on PGF‐2α produced contractions in coronary vasculature. Oxygen consumption increased simultaneously to 143% at 160 μg/ml and then decreased. Myocardial contractility (measured by amplitude and rate of contraction) decreased progressively to about 55% at concentrations from 60–160 μg/ml and further to 20% at 580 μg/ml. Myocardial efficiency expressed as the ratio of contraction rate to oxygen consumption decreased to about 0.2. Heart beat frequency decreased simultaneously to 73%. The electrocardiographic PQ and QRS intervals increased to 143 and 139%, respectively, whereas the QT interval did not increase significantly. Asystolia occurred in some cases at ibuprofen concentrations of 580 μg/ml. The findings suggest that ibuprofen at therapeutic concentrations may possibly produce some coronary vasodilation accompanied by a slight negative inotropic effect. Interactions with other cardioactive drugs seem possible. The drug may cause direct cardiotoxic effects at supratherapeutic concentrations.
Antagonism of Physostigmine Induced Lethality by a Combination of Scopolamine and Methscopolamine
Authors: Janowsky David S. , Berkowitz Alan , Turken Alan , Risch Samuel Craig
Published: July 2010

The antagonistic effects of scopolamine, methscopolamine, and a combination of methscopolamine and scopolamine were evaluated in preventing physostigmine induced lethality in Swiss Webster mice. Low dose scopolamine was found to be highly effective in reversing high dose (3 × the LD100) physostigmine induced lethality, in contrast to methscopolamine, which was ineffective except in very high doses. A combination of scopolamine and methscopolamine was more effective than either drug alone.
Propyl Ether. II. Pulmonary Irritation and Anaesthesia
Authors: Nielsen G. D. , Olsen J. , Bakbo J. C. , Holst E.
Published: July 2010

After cessation of the sensory irritation response, described in part one (Nielsenet al.1985), a mixed response due to pulmonary irritation and anaesthesia appeared, resulting in a decrease in respiratory rate and tidal volume. The corresponding thresholds were 1490 p.p.m. and 1280 p.p.m., respectively, obtained from the last half hour of a four hours exposure period. As the decrease in respiratory rate and tidal volume was found to be correlated, the per cent decrease in respiratory minute volume could be approximated from the square of the respiratory frequency. A threshold limit value (TLV) about 100 p.p.m. based on pulmonary irritation and anaesthesia was proposed. No impurities in the technical grade ether influenced the responses.
Modulation of Choline Transport and Acetylcholine Synthesis in Synaptosomes from Different Brain Regions
Authors: Nordberg Agneta , Sundwall Anders
Published: July 2010

Uptake and biotransformation of radioactive choline (3H‐Ch) have been studied in P2 fractions from different brain regions of mice treated with different doses of sodium pentobarbital (45–120 mg/kg intraperitoneally) or saline. Sodium dependent uptake (SDU) has been measured as the difference between results of incubations with Na+ in the incubation medium and when the sodium salts were replaced by Trisphosphate and sucrose. The uptake of radioactivity increased during the incubation with 3H‐Ch but the proportion of 3H‐ACh was the same at all time points. The proportion of 3H‐ACh to 3H‐Ch in the P2 pellet was 86, 81 and 69 per cent in hippocampus, striatum and cortex, respectively. Omission of sodium ions in the incubation medium reduced uptake of 3H‐Ch by about 90 per cent at 1 μM Ch in the incubation medium and the proportion of 3H‐ACh to 3H‐Ch was only 10 to 20 per cent while the proportion of 3H‐PhCh increased from insignificant amounts to between 20 to 30 per cent. There were quantitative regional differences in SDU, a two times greater uptake was obtained in the striatum compared with cortex and hippocampus. Apparent Km and Vmax were 0.9 × 106 M and 71 pmol/mg, respectively, for the cortex of untreated animals. The contribution of endogenous Ch from the P2 fraction to the incubation medium gave a final concentration of 0.5 μM Ch in the standard uptake experiments. The 3H‐Ch uptake was significantly reduced in P2 fraction from cortex and hippocampus prepared from mice anaesthetized with sodium pentobarbital while the uptake in P2 fractions from the striatum was unaffected. Sodium pentobarbital treatment did not affect the proportion of 3H‐ACh in the pellets.
Chronic Salt Loading and Central Adrenergic Mechanisms in the Spontaneously Hypertensive Rat
Authors: Gradin K. , Elam M. , Persson B.
Published: July 2010

The effects of chronic salt loading on central adrenergic mechanisms were evaluated in spontaneously hypertensive rats maintained on tap water or 1.2% sodium chloride drinking water for 4 weeks. Basal blood pressure was increased by 10% in the high salt group. Central catecholamines were measured spectrofluorimetrically after cation exchange chromatography. Endogenous levels of noradrenaline (NA) were not influenced by salt loading but the NA turnover (disappearance of NA following synthesis inhibition by α‐methyltyrosine) was increased in the hemisperes. Central α2‐adrenoceptor sensitivity was assessed as the clonidine‐induced reduction in blood pressure and as the clonidine‐induced deceleration of NA turnover and locus coeruleus (LC) NA cell firing rate (single unit recording). The results were slightly disparate but the unchanged sensitivity of Clonidine to reduce LC NA cell firing suggests that there were no alterations in central α‐adrenoceptor sensitivity following a salt load. There were also no changes in α‐adrenoceptor function, which was assessed semiquantitatively as the clonidine‐induced increase in flexor reflex activity in spinalized rats. In salt loaded rats there was an enhanced blood pressure and heart rate reduction following ganglionic blockade which may be interpreted as an increased basal sympathetic tone. In the periphery the pressor responses to phenylephrine were increased whereas the chronotropic response to isoprenaline was unchanged. In conclusion, in the spontaneously hypertensive rat on a high salt intake the aggravated development of hypertension was not associated with major changes in central α1and α2‐adrenoceptor mediated functions or in neuronal activity of brain stem NA neurons. There were indications of an increased basal sympathetic tone and increased blood pressure response to pressor substances.
Steric Aspects of Agonism and Antagonism at β‐Adrenoceptors: Experiments with the Enantiomers of Clenbuterol
Authors: Waldeck Bertil , Widmark Erik
Published: July 2010

The enantiomers of clenbuterol, a β2‐selective adrenoceptor agonist with partial agonistic activity, were examined with respect to their ability to reactin vitroon adrenoceptors in the trachea (mostly β2), the soleus muscle (β2) and in the papillary muscle of the left ventricle (β1) from the guinea‐pig. (—)‐Clenbuterol relaxed the carbachol contracted trachea and depressed the subtetanic contractions of the soleus muscle in a concentration‐dependent manner. (+)‐Clenbuterol was at least 1,000 times less potent in this respect. Both isomers inhibited competitively the effect of isoprenaline on the trachea, the (—)‐isomer being about 100 times more active than the (+)‐isomer. None of the isomers showed any detectable positive inotropic effect on the papillary muscle but both inhibited competitively the response to isoprenaline. Also in this respect (—)‐clenbuterol was more potent than (+)‐clenbuterol. It is concluded that the β2‐agonistic as well as the β1‐antagonistic effect of clenbuterol resides in the (—)‐isomer and that the (+)‐isomer does not seem to contribute to the pharmacological effects displayed by racemic clenbuterol.
The Solubility of 2,2,4,4,5,5 ‐Hexachlorobiphenyl in Heparinized Blood and Plasma and In solutions of Different Plasma Components
Authors: Willebrand Tomas , Kihlström Ingemar
Published: July 2010

The solubility of 2,2′,4,4′,5,5‐hexachlorobiphenyl (HCB) in heparinized blood from guinea‐pig, heparinized plasma from mouse and in solutions of Intralipid®, bovine serum albumin (BSA) and in gammaglobulin was examined by studying the equilibrium between HCB adsorbed to a test tube wall and HCB in the aqueous phase. After 24 hours of incubation at 37° the highest concentration of HCB was found in the Intralipid® solution, the lowest one in the gammaglobulin solution. Blood and plasma were able to dissolve equivalent concentration of HCB. One conclusion of these experiments is that the largest part of HCB in blood is bound to albumin. The explanation of different patterns of uptake to solutions of Intralipid and BSA is discussed.
Increased Lead Levels in Brain after Long‐term Treatment with Lead and Dithiocarbamate or Thiuram Derivatives in Rats
Authors: Oskarsson Agneta , Lind Birger
Published: July 2010

Lead concentrations in blood and brain were measured in rats exposed to lead via drinking water, 0.25% Pb (12 mM), and dithiocarbamate/thiuram derivatives administered by gavage singly or in combination for 6 weeks. Sodium salts of diethyldithiocarbamate (DEDTC) and dimethyldithiocarbamate (DMDTC) were given in doses of 0.2 mmol/kg and tetramethylthiuram disulfide (thiram) and tetraethylthiuram disulfide (disulfiram) in doses of 0.1 mmol/kg twice a week. In rats that received lead plus dithiocarbamate/thiuram derivatives lead concentrations in blood and brain were significantly increased; disulfiram being most effective in increasing lead levels, followed by thiram, DMDTC and DEDTC. In blood, lead levels were increased 3‐fold and in brain almost 4‐fold after treatment with lead plus disulfiram compared to treatment with lead alone. When rats were given DEDTC or thiram by gavage (0.1 mmol/kg/day 5 days a week for 2 weeks) after cessation of the lead treatment, there was no increase in blood lead levels but in thiram‐treated rats brain lead concentration was increased 2.7‐fold. In rats treated with DEDTC intraperitoneally after cessation of lead treatment, both blood and brain concentrations of lead were increased. This study suggests that combined exposure of lead and dithiocarbamate/thiuram derivatives causes a substantial increase in brain levels of lead which are not always reflected in increases of blood lead levels. This interaction effect ought to be taken into consideration when evaluating the health effects of environmental and occupational lead exposure.
The Use of Two Different Pharmacological Principles to Inhibit a Cholinergic Bronchospasm in Guinea Pig
Authors: Olsson O. A. T. , Ekdahl A.
Published: July 2010

The ability of inhaled atropine and clonidine to inhibit a bronchospasm produced by injected acetylcholine or by vagal stimulation, was studied in anaesthetized guinea pigs. Vagally mediated airway constriction was restrained in a concentration‐related fashion by inhaled clonidine and reached nearly 100% inhibition (EC50 = 2 × 10−5 mol/l in the nebulizer). Atropine expressed initially about the same level of spasmolytic effect but only a final prevention of 60% was possible to reach with this drug. On the contrary, inhaled atropine was able to produce a complete inhibition (EC50 = 2 × 10−6mol/l) when the bronchoconstriction was elicited by exogenous acetylcholine. This type of spasm was also to some degree inhibited by clonidine.
Influence of Dietary Factors on Aluminium Absorption and Retention in the Brain and Bone of Rats
Authors: Slanina Premysl , Frech Wolfgang , Bernhardson Åsa , Cedergren Anders , Mattsson Per
Published: July 2010

Young adult male Sprague‐Dawley rats were treated by gavage for 10 weeks (3‐times weekly) with aluminium 100 mg/kg b.wt. in the form of Al‐hydroxide (Novalucol), Al‐citrate, Al‐hydroxide together with citric acid or with tap water (controls). Male rats aged 13 months were gavaged for 11 weeks 3‐times a weak with black currant soup (0.8 ml/kg b.wt.) stored 19 days in either aluminium or stainless steel saucepans. The brain cortex, bone and blood (young adults only) of each rat were analysed for Al using graphite furnace atomic absorption spectroscopy. The rats treated with Al‐citrate and in particular rats treated with Al‐hydroxide + citric acid showed a significant increase of Al concentrations in all the tissues studied. In the latter group the mean Al concentrations were elevated at 0.039 μg Al/g wet weight (controls 0.005 μg/g) 0.092 μg/g (0.016 μg/g) and 26.6 μg/g (0.22 μg/g) in the blood, brain and bone, respectively. After treatment with Al‐hydroxide alone only the bone showed a moderate increase of Al‐concentration. No significant differences were found in the brain and bone Al levels of the rats given fruit soup from aluminium saucepans (containing 17 mg Al/l) or stainless steel saucepans (0.4 mg Al/l).
Effect of Nicotine on Passive Avoidance Behaviour and Motoric Activity in Mice
Authors: Nordberg Agneta , Bergh Christer
Published: July 2010

In this study the effect of different doses of nicotine (0.125; 0.250; 0.500 mg/kg) on motoric activity in mice was tested by a T‐maze model both during dark and light phase of the diurnal cycle. Low doses of nicotine (0.125 mg/kg; 0.250 mg/kg) increased motoric activity during the day. During the dark phase no stimulation was seen. A higher dose of nicotine (0.500 mg/kg) decreased motoric activity both during dark and light phase of the diurnal cycle. A positive effect on retention time in a passive avoidance model was observed when mice were pretreated with 0.125 mg/kg nicotine. No significant effect was observed with 0.500 mg/kg nicotine. Thus, a low dose of nicotine which increases motoric activity also seem to have a positive effect on learning/memory mechanisms studied by a passive avoidance behaviour model.
Effects of Maternal Ethanol Consumption on the Offspring Sensory‐Motor Development, Ultrasonic Vocalization, Audiogenic Immobility Reaction and Brain Monoamine Synthesis
Authors: Hård Ernest , Engel Jörgen , Larsson Knut , Liljequist Sture , Musi Barbara
Published: July 2010

Female rats were given 16% ethanol solution as the sole liquid during the entire period of gestation. At birth the offspring was removed and reared by foster dams consuming normal tap water. The development of sensory motor behaviour and emotional reactions was delayed by 1–2 days in the prenatally ethanol exposed pups as assessed by tests on body righting, acoustic startle response, air righting, rearing and ultrasonic vocalization. In the open‐field test the normally occurring behavioural difference between the sexes was not found in the prenatally ethanol exposed pups. Both sexes of the ethanol exposed pups behaved like the female controls suggesting deficient masculinization of the ethanol exposed male pups during foetal age. Biochemical analysis of the brains showed a decreased synthesis of serotonin and dopamine.
Adenylate Cyclase Modulation by Ammonium Ion: GTP‐like Effect on Muscarinic and α2‐Adrenergic Receptors
Authors: Ransnäs Lennart , Hjalmarson Åke , Jacobsson Bo
Published: July 2010

The stimulatory influence of ammonium sulphate on adenylate cyclase activity has been investigated. By competition binding experiments on the β‐adrenergic stimulatory receptor in rat myocardial membranes, no influence could be detected of ammonium sulphate neither in receptor coupling to the stimulatory guanine nucleotide binding protein nor in the GTP‐induced uncoupling. In order to detect an impaired inhibition instead of an increased stimulation of adenylate cyclase activity by ammonium sulphate the investigation was extended to inhibitory receptors. The same type of effect by ammonium sulphate was detected on both the muscarinic cholinergic receptor in rat myocardial membranes as well as on the α2‐adrenergic receptor in human platelets. The influence of ammonium sulphate noted in competition binding studies and off‐kinetics experiments was GTP‐like, i.e. causing a decrease in agonist‐receptor affinity leaving all the inhibitory receptors in the low affinity state. In conclusion, this paper indicates that the observed stimulatory effect of ammonium sulphate is exerted by the ammonium ion on the inhibitory guanine nucleotide binding protein, impairing the negative control of adenylate cyclase activity.
A COMPARISON OF LITHIUM EFFECTS ON HUMAN BRAIN AND RAT BRAIN NORADRENALINE‐SENSITIVE ADENYLATE CYCLASE
Authors: Klein Ehud , Belmaker R.H. , Newman Michael , Gruszkiewicz Jan
Published: July 2010

Abstract:Lithium (Li) is a drug with numerous biochemical effects. Many of these biochemical effects occur only at high Li concentrations, or disappear after chronic Li treatment. Such effects are probably not related to Li's mechanism of therapeutic action. Inhibition of noradrenaline (NE)‐sensitive adenylate cyclase has been proposed as a possible therapeutic mechanism of action for Li. Tolerance does not develop to this effect, which has been reported to occur reliably beginning at 2mM Li in rat cortex. Since 2mM Li is at the upper limit of therapeutic levels in humans, controversy has continued as to whether Li inhibition of NE‐sensitive adenylate cyclase is a mechanism of Li's therapeutic action or a mechanism of Li toxicity. We hypothesized that human brain NE‐sensitive adenylate cyclase may be more sensitive to Li inhibition than rat brain NE‐sensitive adenylate cyclase. Fresh cortical human grey matter was obtained from the edges of surgically removed brain tumors in seven patients. Results showed significant inhibition of NE‐sensitive adenylate cyclase at 1mM Li. These results support the possibility that inhibition of NE‐sensitive adenylate cyclase is a mechanism of Li's therapeutic action.
Preclinical Pharmacology of Diltiazem
Authors: Andersson Karl‐Erik
Published: July 2010

Abstract:The membrane site of action and intracellular effects of diltiazem on heart and blood vessels are briefly discussed and compared to those of other calcium entry blockers, mainly verapamil and nifedipine. Diltiazem seems to have another site of action in the membrane than verapamil and nifedipine. Even if its main action is exerted at the cell membrane level, diltiazem may, at high concentrations, appears to have intracellular effects. Similar to the haemodynamic effects of verapamil and nifedipine, those of diltiazem are determined not only by direct actions on heart and peripheral vessels, but also by sympathetic reflex activity which modulates the direct effects. Two aspects of the myocardial protective action of diltiazem are discussed, the ability of the drug to reduce the frequency of ventricular dysrhythmias associated with ischaemic damage, and the ability to protect the ischaemic myocardium during reperfusion.
Efficacy of Diltiazem for Coronary Artery Spasm
Authors: Schroeder John S.
Published: July 2010

Abstract: The introduction of calcium entry blockers which caused marked vascular smooth muscle relaxation with minimal effects on myocardial contractility have provided a new approach to the patient with angina due to coronary artery spasm. Multiple, double‐blinded, randomized studies of diltiazem versus placebo have demonstrated that this agent results in reduction in angina frequency and nitroglycerin consumption by 30% to 70% with a demonstrated dose response. A long‐term, open label follow‐up study of 18 patients who participated in a 44‐week prospective, double‐blind crossover trial of 240 mg of diltiazem versus placebo for prophylaxis of angina in patients with coronary artery spasm demonstrated a 75% decrease in angina attacks during the first five months of the study and an 80% decrease compared to the placebo period during the second six months. Both the short‐ and long‐term studies have demonstrated very few adverse side effects, less than 7%. A recent long‐term study of 43 patients who took diltiazem regularly and were followed in the Coronary Artery Spasm Clinic at Stanford University Medical Center for a mean of 19.6 months (range 6 to 28.5 months) was analyzed for cardiovascular events in the 19.6 months prior to therapy and the 19.6 months after the initiation of therapy. Cardiovascular events on diltiazem, including sudden cardiac death, myocardial infarction, and hospitalization to rule out myocardial infarction utilizing a binomial distribution showed over a 90% reduction compared to the pre‐diltiazem period. Adverse effects were reported in six patients who reported minimal to mild pedal oedema. We concluded on the basis of these studies that diltiazem is effective not only for the short‐ and long‐term prophylaxis of angina pectoris in patients with documented coronary artery spasm, but it may reduce the frequency of new cardiovascular events when used on a regular basis. Furthermore, it is nearly free of adverse side effects and there was no evidence of tolerance or tachyphylaxis developing during the study.
Metabolism of Benzo(a)pyrene in the Nuclear and Microsomal Fractions from Rhesus Monkey Liver
Authors: Pacifici G. M. , Blanck A. , Rane A.
Published: July 2010

Abstract:The metabolism of benzo(a)pyrene was studied in the nuclear and microsomal fractions from four rhesus monkey livers. The nuclear fraction was obtained by differential centrifugation, including a step in 2.3 M sucrose. The metabolites from3H‐benzo(a)pyrene were separated by high performance liquid chromatography (HPLC) and the radioactivity was measured. The nuclear fraction catalyzed the formation of 4,5‐ and 7,8‐dihydrodiols and that of 9‐OH and 3‐OH phenols. The ratio between the nuclear and microsomal rate of formation of the metabolites ranged between 0.02 and 0.03. The nuclear fraction did not catalyze the formation of 9,10‐dihydrodiol or quinones at a detectable rate. In the microsomal fraction there was a preferential formation of 4,5‐dihydrodiol and 3‐OH phenol. Nuclei differ from the microsomes for the lack of formation of quinones.
Oesophageal Ulcerations and Plasma Levels of Different Alprenolol Salts: Potential Implications for the Clinic
Authors: Olovson Stig‐Göran , Havu Nülo , Regårdh Carl‐Gunnar , Sandberg Anders
Published: July 2010

Abstract: The ulcerogenic effect of five different salts of alprenolol were tested against placebo in a porcine oesophageal test model. The salts with high water solubility, such as the hydrochloride and the fumarate, gave rise to the highest plasma concentrations of alprenolol and evoked serious oesophageal lesions, while the salts with low solubility – the benzoate, maleate and sebacate – had no irritative effect on the oesophagus. The plasma levels of alprenolol were much higher following administration of alprenolol hydrochloride in the oesophagus than after an identical intraduodenal dose of the same salt possibly because of the avoidance of the first‐pass degradation during oesophageal absorption.
Drug Metabolism and Metabolite Transport in the Small and Large Intestine: Experiments with 1‐Naphthol and Phenolphthalein by Luminal and Contraluminal Administration in the Isolated Guinea Pig Mucosa
Authors: Sund* Reidar Bredo , Lauterbach Fritz
Published: July 2010

Abstract:The metabolism and metabolite transport of the monophenol 1‐naphthol (I) and the diphenol phenolphthalein (II) have been studied in a symmetrical setup of the isolated jejunal and colonic mucosa from the guinea pig (Lauterbach 1977). In both tissues, the main metabolites of I were its sulphoconjugate and glucuronide, but the rate of metabolism, relative proportion of the metabolites and their distribution pattern varied with tissue and drug administration side in the following manner: By luminal administration (50 nmol/ml) in the jejunum, the metabolism was nearly complete within 45 min., more sulphate (1.5–3x) than glucuronide was formed, and both metabolites were predominantly transferred back to the lumen. By blood‐side administration, the metabolism was less complete due to a significant decrease of the sulphated fraction. In concequence, more glucuronide (1.5–3x) than sulphate was formed. Moreover, the efflux pattern of the metabolites changed completely; the greater part of the glucuronide fraction now being conveyed to the blood side, whereas the sulphate tended to distribute in a 1:1 fashion on the lumen and blood side. The colonic mucosa behaved in a dissimilar way, since neither I metabolism nor metabolite efflux pattern in this tissue was influenced significantly by drug administration side. More sulphate (1.5–3x) than glucuronide was formed by both routes, and the metabolite distribution was similar to that observed by blood side administration in the jejunum. The changes described above were associated with changes in tissue accumulation of free I and metabolites; accumulation of I by luminal administration in jejunum was insignificant and that of the metabolites small. The main change caused by a higher concentration of I (130 nmol/ml) was a decrease in the sulphated fraction in the colon. II was metabolized at a slower rate than I, and a significant tissue accumulation of free II was observed in all instances. The monoglucuronide was the main metabolite. Only minor amounts of II monosulphate were formed, making its distribution pattern difficult to ascertain. The distribution of II monoglucuronide on the other hand was generally similar to that described for its I analogue.
Distribution of β‐Adrenoceptor Blocking Drugs into Cerebrospinal Fluid in Rats
Authors: Ylitalo Pauli , Lindén Inge‐Britt , Penttilä Aneri , Vapaatalo Heikki
Published: July 2010

Abstract:The distribution into cerebrospinal fluid (CSF) of five3H‐ or14C‐labelled β‐adrenoceptor blocking drugs given intravenously was studied in urethane‐anaesthetized rats. The doses (mg/kg) were: alprenolol 5, metoprolol 1, oxprenolol 5, pindolol 0.5, propranolol 0.1 and 5. Within 15 min. a marked fraction of the given radioactivity appeared in CSF with all substances. During the follow‐up period of 315 min., only propranolol, independently of dose, caused high CSF/plasma ratios (0.54–0.73) of radioactivity. The other four β‐adrenoceptor blocking drugs caused levels of CSF radioactivity which were 0.05–0.28 of that in plasma and 0.05–0.14 of the calculated levels of activity in the whole body. Since propranolol is bound to plasma proteins to a higher degree than the other drugs studied, the penetration of the unbound fraction of propranolol into rat CSF is even more pronounced than what would be expected on the basis of CSF/plasma ratio measured.
Interactions between Hexobarbital and Thiopental in Male Rats Evaluated with an Anaesthesia Threshold
Authors: Norberg Lennart , Wahlström Göran
Published: July 2010

Abstract:The anaesthetic interaction between hexobarbital and thiopental in different combinations were investigated in male rats by using the isobolografic method. Data on dose, serum or brain concentrations at an EEG‐criterion induced with a threshold method were utilized. The criterion was defined by a burst suppression in the EEG of 1 sec. or more (the “silent second”). With rats more than 115 days of age a synergistic interaction (potentiation) was obtained when a low dose of hexobarbital and a high dose of thiopental were used. The relationship between serum and brain concentrations of hexobarbital and thiopental in the different tested combinations gave no evidence for a pharmacokinetic interaction. Thus the synergistic interaction was located in the brain and probably related to the mechanisms of action. The same tests performed on rats at an age of approximately 90 days gave not only a potentiation when a low dose of hexobarbital and a high dose of thiopental were used, but also a potentiation when a high dose of hexobarbital and a low dose of thiopental were used. These results indicate an age‐related change in sensitivity in the CNS between 90 and 115 days of age. Further investigations of this age‐related change showed that this change from a potentiation to an additive interaction occurred between the age of 85 and 96 days.
Trichloroacetic Acid Accumulates in Murine Amniotic Fluid after Tri‐ and Tetrachloroethylene Inhalation
Authors: Ghantous H. , Danielsson B. R. G. , Dencker L. , Gorczak J. , Vesterberg O.
Published: July 2010

Abstract: The distribution of trichloroethylene (Tri) and tetrachloroethylene (Tetra) and their metabolites have been studied in pregnant mice by means of whole‐body autoradiography (14C‐labelled Tri and Tetra) and gas chromatography, with special emphasis on possible uptake and retention in the foetoplacental unit. Volatile (non‐metabolized) activity appeared at short intervals after a 10 min. or 1 hr inhalation period in foetus and amniotic fluid. Most notable, however, was a strong accumulation and retention (peak at 4 hrs) in amniotic fluid of the metabolite trichloroacetic acid (TCA) after inhalation of either of the solvents. The main metabolite of Tri, trichloroethanol (TCE) (or conjugates), did not accumulate specifically as compared to maternal plasma. TCA infused intravenously in the maternal plasma was accumulated in amniotic fluid, but less pronounced than after Tri and Tetra inhalation, indicating that some metabolism of Tri and Tetra to TCA may occur in the foetoplacental unit. The results suggest that TCA may be transported to the foetus partly paraplacentally through foetal membranes and amniotic fluid, with the possibility of foetal swallowing or absorption through the skin. Foetal urinary activity also suggests that circulation between foetus and amniotic fluid may contribute to the long‐term retention in the foetoplacental unit. In the mother, after inhalation exposures, and in intraperitoneally injected newborn mice, non‐extractable radioactivity was found in the respiratory tract, liver, and kidney, indicating binding to these organs through metabolism.
Rubidium Uptake by Mouse Pancreatic Islets Exposed to 6‐Hydroxydopamine, Ninhydrin, or other Generators of Hydroxyl Radicals
Authors: Grankvist K. , Seblin J. , Täljedal I.‐B.
Published: July 2010

Abstract:The purpose was to study the toxicity of drugs known to generate free radicals on isolated pancreatic islets. The accumulation of86Rb+by mouse pancreatic islets was measuredin vitro.Exposing the islets to 6‐hydroxydopamine, ninhydrin, or phenazine methosulphate + NADH inhibited the Rb+uptake, whereas paraquat or acetylphenylhydrazine had no effect. This effect of 6‐hydroxydopamine was prevented by either of the hydroxyl radical scavengers, sodium benzoate and mannitol, but not by the non‐scavenger, urea; ninhydrin was partially protected against by mannitol but not by benzoate. Protection against 6‐hydroxydopamine was also afforded by D‐glucose but not by L‐glucose or 3‐O‐methyl‐D‐glucose; none of the sugars protected against ninhydrin. In damaging islet beta‐cells and in being protected against by D‐glucose, 6‐hydroxydopamine closely resembles the diabetogenic drug, alloxan. It is suggested that protection against alloxan may involve both glucose metabolism and the interaction of glucose with its membrane‐located carrier, while protection against 6‐hydroxydopamine appears to be unrelated to the hexose carrier mechanism.
Partial Agonism and Functional Selectivity: A Study on β‐Adrenoceptor Mediated Effects in Tracheal, Cardiac and Skeletal Muscle
Authors: Waldeck B. , Jeppsson A.‐B. , Widmark E.
Published: July 2010

Abstract:Colterol, procaterol, sulfonterol, terbutaline and three monophenolic derivatives of terbutaline were examined with respect to their ability to reactin vitroon β‐adrenoceptors in tissues isolated from guinea‐pig. The effects measured were a) relaxation of the tracheal smooth muscle (mostly β2), b) depression of subtetanic contractions of the soleus muscle (β2), and c) increase in the force of the papillary muscle of the left ventricle (β1). Antagonistic effects were measured against isoprenaline as an agonist. The compounds studied showed a wide variation in selectivity, potency and intrinsic activity. All agonists showed a pronounced β2‐selectivity, in general characterized by a higher intrinsic activity at β2‐ than at β1‐adrenoceptors, while differences in affinity, as judged from the pA2‐values were small. Partial agonists, such as sulfonterol, which did not cause a complete relaxation of a moderately contracted tracheal muscle, produced identical concentration‐response curves from the trachea and soleus muscle. It is concluded that partial agonism at β1‐adrenoceptors is an important factor for functional selectivity of β2‐adrenoceptor agonists. On the other hand there seems to be no useful differences between the maximum effect elicited by a partial β2‐adrenoceptor agonist on the skeletal muscle as compared with airway smooth muscle.
Effects of Methyl Mercury on Sperm Oxygen Consumption
Authors: Mohamed Mostafa K. , Evans Timothy C. , Mottet N. Karle , Burbacher Thomas M.
Published: July 2010

Abstract: Oxygen consumption and percent motile spermatozoa were determined for semen samples from healthy male monkeys Macaca fascicularis. Methyl mercury was added to the samples, in the oxygen measurement chamber, at a concentration of 9 p.p.m. for 15 min. and then increased to 15 p.p.m. for 15–30 min. Oxygen consumption and percent motility were determined during each period. Methyl mercury addition resulted in decreased sperm motility, but we did not detect any inhibition in the rate of oxygen consumption accompanying the decreased motility. On the contrary, the rate of oxygen consumption increased at 15 p.p.m. within 15 min., while the sperm motility was close to zero. Antimycin inhibited the increased rate of oxygen consumption demonstrating the mitochondrial source of this increased rate. Oligomycin also inhibited the increased rate of oxygen consumption due to methyl mercury, thus excluding the possibility of uncoupling of mitochondrial oxidative phosphorylation. Interference with mitochondrial energy production does not seem to be the primary mechanism of methyl mercury‐induced decreased spermatozoal motility. Methyl mercury interference with the dynein/microtubule sliding assembly now seems to us to be a more tenable hypothesis.
The Degree of Analgesia Correlates to Spinal Morphine Concentration after Intrathecal Administration in Rats
Authors: Gustafsson Lars L. , Post Claes
Published: July 2010

Abstract:Antinociceptive effects of intrathecal injections of morphine and pethidine were evaluated in rats using the hot‐plate and tail‐flick tests. Both drugs elicited antinociceptive effects either it was evaluated with maximal response latency (sec.) or with area under the curve (AUC) (sec. × min.). The effects of pethidine were shortlived. The concentration of morphine in the spinal cord correlated to its antinociceptive effects when tested on hot plate. A minimal morphine concentration of 3 pmol/mg in the spinal cord was required to induce experimental analgesia in the rat.
Metabolic Interaction between Morphine and Various Benzodiazepines
Authors: Pacifici Gian‐Maria , Gustafsson Lars L. , Säwe Juliette , Rane Anders
Published: July 2010

Abstract:The interaction between benzodiazepines and the glucuronidation of morphine was studiedin vitroandin vivo.All benzodiazepines tested (diazepam, N‐desmethyldiazepam, oxazepam, lorazepam, clonazepam, nitrazepam and flunitrazepam) inhibited the glucuronidation of morphinein vitroin rat liver microsomes. Clonazepam was the most and nitrazepam the least powerful inhibitor, reducing the rate of morphine conjugation by 86% and 42% of the control, respectively, at a substrate and inhibitor concentration of 1.5 mM. Rats given a single oral dose of oxazepam (20 mg per kg body weight) one hour prior to an intraperitoneal dose of morphine (10 mg per kg body weight) had a lower morphine glucuronide/morphine concentration ratio in the 24 hour urine portion than control rats without pretreatment with oxazepam. These data indicate that oxazepam inhibits the glucuronidation of morphine in ratsin vivoas well asin vitro.
The Pharmacokinetics and Protein Binding of Disopyramide in Pigs
Authors: Pedersen L. E. , Hermansen K. , Olesen H. P. , Rasmussen S. N.
Published: July 2010

Abstract:The pharmacokinetics of disopyramide were investigated in 5 pigs. Disopyramide was administered as intravenous bolus injections at different doses and as intravenous infusions at different rates. By measuring the free and total concentrations in plasma of parent compound and desisopropyldisopyramide (the main metabolite in humans) and the amounts excreted in urine it was found that disopyramide had a concentration dependent protein binding and that free and total concentrations could be described by a two‐compartment model with a t1/2,βof approximately 2 hours. The free concentrations were found to be more valuable for estimating the kinetic parameters. The total clearance of disopyramide in the pig was found to approximately 3 ml/min./kg which is about 3 times greater than in man. In contrast to humans the free clearance in the pig increased with declining concentration. Apart from this the kinetics of disopyramide in the pig were very similar to those in man. In conclusion the pig could be a relevant model for studying the pharmacokinetics in humans.
Effects of 1,1,1‐Trichloroethane on the cGMP Metabolism in Mouse Brain
Authors: Nilsson Karin B.
Published: July 2010

Abstract:Administration of 1,1,1‐trichloroethane (TCE) to mice by inhalation or intraperitoneally reduced the cGMP contents of the brain stem, cerebral cortex, and vermis anterior, including the hemispheres. Following intraperitoneal administration the cGMP contents of the vermis posterior and hippocampus were also reduced. To investigate the mechanism underlying these changes, the effects of TCE on brain guanylate cyclase (GC) and phosphodiesterase (PDE) activities were examined after intraperitoneal administration in mice. The basal GC activities in the particulate and soluble fractions of the homogenates of the cerebellum, brain stem and cerebral cortex were not altered by TCE. In the cerebellum TCE treatment inhibited sodiumazide‐stimulated GC activity in the particulate and soluble fractions, while in the brain stem it enhanced the particulate GC activity induced by Ca2+. TCE treatment increased the rate of cGMP hydrolysis in the cerebral cortex and this was further accelerated by addition of Ca2+. Ca2+also increased the rate of cGMP hydrolysis in the brain stem. However, in the cerebellum TCE enhanced the Ca2+‐independent PDE activity as well as the enzyme activity in the presence of Ca2+and exogenous calmodulin. These results indicate that the reduction of the cGMP content in the brain stem and cerebral cortexin vivoon exposure to TCE is due to changes in the rate of cGMP hydrolysis. In the cerebellum the TCE reduced cGMP content may be regulated by increased rate of cGMP hydrolysis as well as effects on the guanylate cyclase.
Cold Hands after Exposure to Arsenic or Vibrating Tools: Effects of Ketanserin on Finger Blood Pressure and Skin Temperature
Authors: Lagerkvist Birgitta E. , Linderholm Håkan
Published: July 2010

Abstract:The effect of ketanserin, a serotonin 5‐HT2receptor inhibitor, on the cold‐provoked vasospasm in arsenic workers was examined by measuring the finger systolic pressure (FSP). After injection of 10 mg ketanserin the skin temperature and the FSP of the cooled finger increased significantly. Prolonged oral treatment with ketanserin, 2 × 40 mg per day, did not significantly influence the skin temperature or FSP during local cooling in arsenic workers or patients with primary or vibration‐induced Raynaud's phenomenon. The effect of ketanserin intravenously indicates that serotonin is involved in the mechanism behind vasospasm of arsenic workers in the same way as it is known to be in patients with primary and vibration‐induced Raynold's phenomenon.
Effect of Detomidine on the Release and Turnover of Noradrenaline in Rat Brain
Authors: Virtanen Raimo , MacDonald Ewen , Kaisila Maiju
Published: July 2010

Abstract: The effect of detomidine, a novel veterinary sedative/ analgesic, on the release and turnover of noradrenaline in rat brain was studied using both in vitro and in vivo techniques. Xylazine was included in the studies for comparison. Rat occipital cortex slices were preloaded with 3H‐noradrenaline and the potassium‐evoked release of tritium was measured using a superfusion system. Both detomidine and xylazine produced concentration dependent inhibition of stimulation evoked tritium release. A maximal inhibition of 66 and 50% was achieved at detomidine and xylazine concentrations of 1 × 10−7 and 1 × 10−6M, respectively. The dose‐response curve of detomidine was shifted to the right in a parallel manner by the selective α2‐antagonist idazoxan. Detomidine, while not altering the endogenous levels of noradrenaline, dopamine and 5‐hydroxytryptamine, induced a dose‐dependent inhibition of noradrenaline turnover as measured by the α‐methyl‐p‐tyrosine method. Moreover, detomidine decreased the concentration of MHPG‐SO4, the principal metabolite of central noradrenaline, in rat brain. Xylazine was in these tests at least two orders of magnitude less potent than detomidine.
Preventive and Therapeutic Effects of Thiamine, Ascorbic Acid and Their Combination in Lead Intoxication
Authors: Flora S. J. S. , Tandon S. K.
Published: July 2010

Abstract: Thiamine, ascorbic acid and their combination were investigated for their ability to prevent or treat the experimental lead intoxication in rats. The combination of the two vitamins was most effective in reducing the lead induced inhibition in the activity of blood δ‐aminolevulinic acid dehydratase, elevation in the level of blood zinc protoporphyrin and the urinary excretion of δ‐aminolevulinic acid and the uptake of lead in blood, liver and kidney. The combined treatment post lead exposure was also most effective in restoring the lead induced biochemical alterations and mobilizing lead from the tissues. The order of effectiveness was, thiamine + ascorbic acid < ascorbic acid < thiamine. The lead induced changes in brain biogenic amines and the brain concentration of lead remained unaffected by these vitamins.
Felodipine, Pharmacodynamics and Pharmacokinetics in the Isolated Rabbit Heart
Authors: Askholt J. , Nielsen‐Kudsk F.
Published: July 2010

Abstract:Myocardial pharmacodynamics of the Ca2+‐antagonist felodipine, a structural analogue of nifedipine, were studied in isolated, spontaneously beating and retrogradely perfused rabbit hearts. The concentration of felodipine in the Krebs‐Henseleit perfusion liquid was stepwise increased from 0.7 ng/ml to 90.4 ng/ml (1.8 to 235.3 nmol/l). Increasing felodipine concentrations from 0.7 to 3.6 ng/ml produced an increase of up to 115% in coronary flow rate, which then decreased at higher concentrations to 84% of the control value. Oxygen consumption decreased progressively to 28% at concentrations from 3.6 to 90.4 ng/ml. Myocardial contractility measured by amplitide and rate of contraction decreased progressively to 45.7 and 41.5%, respectively, at concentrations from 0.7 to 9.4 ng/ml and further to 4.0 and 3.0%, respectively, at 90.4 ng/ml. Myocardial efficiency expressed as the percentual ratio of contraction amplitude times frequency to oxygen consumption decreased to 11% at the highest concentration of felodipine. Heart beat frequency decreased simultaneously to 45.6%. The electrocardiographic PQ and QRS intervals increased at the highest concentration to 174 and 111%, respectively, whereas the QT interval decreased to 86.6%. Asystolia occurred in several cases at felodipine concentrations of 90.4 ng/ml. Both myocardial accumulation and disposition pharmacokinetics of the drug showed one‐compartment characteristics with half‐lives of about 97 min. for both processes. Apparent Vdwas about 480 ml/g myocardial tissue, which expresses a very pronounced binding and accumulation of felodipine in the rabbit myocardiumin vitro. The findings demonstrate that lower concentrations of felodipine produces coronary vasodilation in the isolated rabbit heart accompanied by a marked negative inotropic effect and a less than proportional reduction in oxygen consumption. The drug seemed to cause direct cardiotoxic effects at higher concentrations.
The Analgesic Effect of Buprenorphine, Etorphine and Pethidine in the Pig: A Randomized Double Blind Cross‐over Study
Authors: Hermansen K. , Pedersen L. E. , Olesen H. O.
Published: July 2010

Abstract:In order to find a suitable analgesic for the treatment of postoperative pain in pigs the analgesic effect of buprenorphine, etorphine and pethidine has been compared in 8 domestic pigs. For assessment of the analgesic action one thermal (hot plate) and two mechanical (cannulation of ear vein, needle prick) noxious stimuli have been employed. In a pilot experiment on 2 pigs in which methadone was included the maximal effective doses were estimated for each drug. Methadone was found unsuitable because of unacceptable side effects (respiratory dysfunction, hyperactivity) at effective dose levels. Next buprenorphine 120 μg/kg, etorphine 3 μg/kg and pethidine 20 mg/kg all given intramuscularily were compared in a randomized blind trial with a balanced cross‐over design on 6 pigs. Etorphine proved to have the highest and pethidine the lowest maximal analgesic effect which was especially evident in the needle‐prick test. Buprenorphine proved to have the longest duration of action in all three analgesic tests, in the hot plate test lasting between 7 and 24 hrs. Etorphine had a duration of 3 to 5 hrs whereas the effect of pethidine was short, only lasting about 2 hrs. Etorphine provides a complete analgesia but has a small safety margin for which reason it should be used with caution in the pig. The experimental results indicate that buprenorphine should be the first drug of choice in the treatment of pain after surgical intervention due to its long duration of action and lack of side effects.